Ben is helping Reed to test out Sue's new force field, when they start receiving complaints from the Baxter Building's other tenants. Reed decides to take the team's tests to an isolated island that he was alerted to by a leaflet mailed to him. When the Four get to the island, the team is stranded there when their U-Car is stolen. They then run into the Mole Man, the ruler of Subterranea, who tells them that he has rebuilt his underground network of tunnels leading to every capital city. He intends to take over the world's governments, and to accomplish this, imprisons each of the Four in a series of traps. The Four have to escape their confinement and prevent the Mole Man from taking over the world.

The Fantastic Four are lost in a Transylvanian forest while on vacation, and eventually come across an old castle. They are warned that the castle belongs to Diablo, an evil alchemist was was sealed away in the dungeon exactly 100 years ago.

Dr. Doom heads towards New York, claiming diplomatic immunity. Sue and the police commissioner summon all the team members to the Baxter Building, where the Fantastic Four prepare for Doom's arrival. There, they get a message from Doom, who tells Reed that he should say goodbye to his team-mates as he only has a few hours left to live. The commissioner asks Reed why Doom hates him, and he tells him of how he and Victor von Doom used to be at the same college years ago. Ben was also there, becoming Reed's roommate, while Doom conducted a dangerous experiment that scarred his face. Doom was expelled, and blamed Reed for his disfigurement. Doom vanished, while Reed and Ben served their time in World War II. After the war, Reed developed a starship, and chose Ben to pilot it, with Sue and Johnny as the rest of the crew. During their first flight, the starship was bombarded with cosmic rays that gave the team their super-powers and turned them into the Fantastic Four.

On the Skrull homeworld, the Skrull emperor attempts to destroy the Fantastic Four, but Sue protects them with her invisible shield. Marshall Drom then shows the emperor a new weapon that will not fail: the Super Skrull, who has all the powers of the Fantastic Four. He is sent to Earth, where he quickly comes into contact with the super-hero team in New York. After claiming the Earth in the name of the Skrull Empire, Super Skrull and the Fantastic Four battle each other, but are too evenly matched. The Four then retreat back to the Baxter Building, where Reed discovers that Super Skrulls powers are being beamed to him from the Skrull homeworld. Reed creates a jamming device, and after inviting Super Skull to fight the team on Crater Island, Sue has to attach the jammer to Super Skrull before the rest of the team can stop him.

Reed is exploring sub-space with his equipment while Johnny takes a vacation. Soon however, Klaws, the master of sound arrives at the Baxter Building and attacks the remainder of the team with sonic booms. He traps Reed and Ben with a wall of solid sound waves, but Ben breaks through. Klaws tries to get Sue to call back Johnny, but she resists, and Ben attempts to stop him. Klaws defeats Ben with another sonic blast, but Johnny returns with vibranium bands after Reed gets a message to him. Now all assembled, the Fantastic Four then does battle with the powerful Klaws.

Reed experiments on a meteor for use as a new super fuel, but with little success. He got the idea from a scientist named Professor Ivan Kragoff, and so the Four endeavour to use the fuel to get to the Moon, winning the space race before Kragoff, and to explore a mysterious blue area on the Moon's surface. Kragoff himself, known as the Red Ghost, uses a trio of intelligent apes to assist him in his rocketship. Both ships take off at the same time, and the Red Ghost's ship is bombarded with cosmic rays, giving him and his apes super powers. In the Moon's blue area, the team find an ancient deserted city, and come under attack from the Red Ghost and his super apes. Sue is taken hostage, and Reed, Ben and Johnny follow the Red Ghost for the final battle.

A U.F.O. appears over the Earth, and after the air force attempt to intercept it, the craft's robot pilot abducts the Fantastic Four from an awards ceremony. Inside the spaceship, they are told by the robot that they are to be taken to Planet X by order of Kurrgo, the planet's master. Kurrgo tells the team that his planet is due to be struck by a rogue planet. In order to prevent his slaves from being killed, Kurrgo asks Reed to find a way of saving his workforce. The Four refuse his request, but Kurrgo forces them to work in his lab. There, Reed determines that the other planet is due to strike Planet X in less than a day. Reed decides to use a shrinking gas to reduce all of the population in size so that they will all fit on the two available escape ships and be saved. Reed shows the gas to Kurrgo, and promises to develop an antidote before the planets collide. As Planet X's population is shrunk, the Four have to return to Earth and end the dictator Kurrgo's rule.

As the Fantastic Four answer the Yancy Street Gang's challenge to Ben, they quickly discover that it was a trap, and are attacked by three mutant apes. The Red Ghost then appears, having escaped from the Moon, and takes the Four back to the Moon in his rocketship. He jettisons the team to the Moon's surface, and with the help of Sue's force field, quickly attempt to make their way to the inhabitable blue area of the Moon. They end up inside the underground home of the Watcher, who tells them by thought-image that he cannot help them against the Red Ghost, and warns them not to touch any of the machines in his lab for their own safety. Meanwhile, the Red Ghost hold the world to ransom, but his rocket is soon brought back down to the Moon by Reed. The Red Ghost follows Johnny back to the Watcher's base, and there, the Four have to stop the villain and his super apes.

Dr. Doom appears on the Fantastic Four's TV, and challenges them to a duel to the finish. He predicts that he will remove the heart of the team, remove the team's greatest strength and finally, that the strongest power will conquer all. As Sue takes part in a photo shoot, Doom kidnaps her and takes her to his base, thus removing the team's heart. The rest of the team take part in a conference at the U.N., where Doom announces that he will destroy every major city on Earth with tidal waves unless he is voted world ruler. He demonstrates his power on an abandoned navy yard, and tells the team not to stop his plans as he has Sue. Reed tracks down Doom's airship, and the team go there to rescue Sue. On board, Doom attacks them with a cosmic ray gun, and turns Ben back to his human form, removing the team's greatest strength.

On the Skrull homeworld, Warlord Morat is out hunting game when he decides to capture the Fantastic Four in order to impress Princess Anelle's father, the emperor of the Skrulls. The Four themselves are testing out Reed's new rocket, when it is bombarded by meteorites controlled by Morat. They are pulled through a space-warp and end up in the Skull's galaxy. Upon their arrival, the Four are attacked by Morat's Skrull soldiers. They defeat the Skrulls, but soon lose the use of their powers due to an immobilising ray. They are taken to Morat's base and held captive. Swearing to deliver the Four to Anelle's father, Morat instead attempts to overthrow the emperor with the quartet's aid. As the Skrull emperor journeys to Morat's base to find out what is going on, Morat is told by Reed to use a special ray-gun from his ship. The rest of the team object, but Reed asks them to trust him. Morat uses the weapon on the Four and inadvertently restores their powers.

Reed has been elected to ask the villainous Professor Gamma to surrender himself and to destroy his Island X base in order to answer for his crimes against the world. Reed and the rest of the Four then attack the island and defeat the Professor's henchmen, destroying the Professor's nuclear missiles. Gamma himself was not on the island and due to the radiation released from his nuclear warhead, is mutated into an amphibious form and now calls himself the Gamma Ray. Johnny, having been told to rest after the last mission, gets angry and leaves the team, staying in a slum hotel. There, he is told a tall tale by one of the residents who says that he saw a strange creature at sea calling himself the Gamma Ray the other day. Suspecting a link to Professor Gamma, Johnny decides to investigate for himself and quickly finds Gamma Ray. They fight, and Gamma Ray then mutates a giant whale into a creature named Giganto, who then begins to walk towards New York.

Johnny is testing his ability to throw flares when he notices a strange object emerging from the sea. A blue-skinned woman emerges and introduces herself as Lady Dorma of Pacifica. She asks the Fantastic Four for help in fighting the tyrant Attuma, whom she inadvertently allowed to defeat the kingdom's rightful ruler, Prince Triton. Realizing her mistake, she sought out the help of the Four to help stop Attuma's conquest. Reed uses an oxy-spray to help the team breathe underwater, and together with Dorma they journey to Pacifica. They proceed to battle Attuma's forces and make their way into the royal palace. There, the meet up with Prince Triton and assist him in his struggle against Attuma and his forces.

An earthquake rocks New York, and Johnny spots that the whole city block has disappeared into the Earth's surface. Reed quickly deduces that this was the work of the Mole Man. The villain himself sinks Science Hall where Sue was giving a speech to a group of leading scientists, and tells the rest of the team not to interfere with his plans. Reed, Ben and Johnny descend into the Earth's surface to the Mole Man's subterranean hideout, but after he threatens Sue, the team are returned to the surface to warn off the national guard from attacking his base. Back at the Baxter Building, Reed develops a tracker to find Sue, and Johnny digs a tunnel for Ben and Reed's hover-cycle to travel down. After freeing Sue, the now-reunited Four have to fight the Mole Man and his forces in order to free all of his hostages and raise the missing buildings.

Ben is insulted by the Yancy Street Gang and becomes depressed over his appearance. The rest of the team visit an Egyptian museum and find an ancient tablet apparently depicting Ben returning to his human form. Reed tells him about the tablet, and the Four travel to Dr. Doom's castle to use time machine to travel back to 10th Century B.C. Egypt. There, they quickly come under attack by soldiers, but Reed notices that their attire is from another time. The team then all pass out, and are taken to Rama-Tut, ruler of Egypt. He tells them that he is from the year 3000, and seeking adventure, constructed a time machine and travelled back to ancient Egypt. He imprisons the team as hypnotised slaves, but a passing comet returns Ben to his human form and restores his will. As Rama-Tut prepares to marry Sue, Ben rescues her and the rest of the team. As the comet moves away, Ben becomes the Thing again, and the Four follow Rama-Tut for their final confrontation.

Another Sun suddenly appears in the sky, which soon disappears and gives way to millions of floating rocks in the sky. A being known as the Watcher appears to the team and tells them that he caused the illusions, trying to hide the Earth from the Silver Surfer, a being who serves Galactus, who drains planets of their energy. Unfortunately, the Surfer finds the Earth and signals Galactus, who quickly announces that he will drain this world as he has done others. Ben knocks out the Surfer, who is then found and looked after by Sue, while the rest of the team try to fight Galactus. As Sue cares for the Surfer, who quickly begins to appreciate humanity, Galactus begins construction of his Elemental Convertor to drain the Earth's energy. The Watcher sends Johnny on a journey to Galactus' space station to retrieve a weapon known as the Ultimate Nullifier, and the Silver Surfer decides to betray his master and assist the Fantastic Four in defeating Galactus.

Whilst Ben is delivering a piano across town, he starts shrinking until only a couple of inches tall. The same thing happens to Sue while out shopping, Reed while testing a new aircraft and Johnny while fixing his car. They all eventually make it back to the Baxter Building where they hear a voice warning them to beware Dr. Doom. The Four are nearly sucked into an air vent, while Doom and his captive, Princess Pearla watch. The team escape thanks to Johnny's help, and are then shrunk further until they end up on a micro world controlled by Doom. The fight Doom's new army, but he shrinks them even further and tells the team how he accidentally discovered and subsequently conquered the micro world. Now captured by Doom, the miniature team meet up with the King and his daughter. In their prison, Doom tells the team of how he will use lizard-men from a nearby micro world to help him in his conquest of the micro-universe. The Four must escape their confinement and stop Doom's plans.

Reed uses his time-space dimension machine to observe a strange distant planet in the midst of a giant battle. The planet's inhabitants are fighting Blast Starr, an incredibly powerful being capable of throwing power bolts from his hands. He is eventually defeated using a special gas and exiled to outer space in a capsule suit. Reed uses his machine to enter the Negative Zone and look closer at the planet, but ends up trapped there with no return. He asks Johnny to follow him to halt his journey through space, and with his help, Reed is returned to Earth, along with Blast Starr, who escapes from his capsule suit. On Earth, Blast Starr begins destroying everything in sight, and the Four attempt to stop him. They trick him into believing that he has destroyed them, and then lure him to an atomic power plant on Atlantis island where the final battle takes place.

A meteor from deep space lands on a remote farm, and after Reed studies it back at the Baxter Building, he discovers that it has energy-absorbing properties. As the meteor is sealed in the lab's vault, the team notice a strange green glow outside, and an individual calling himself the Molecule Man performing seemingly impossible feats.

An alien ship from deep space approaches Earth and abducts the Fantastic Four. The robotic crew take the super-team to their world, where Reed is informed that he and the rest of the Four are being charged with crimes against evil, with the team's accusers being Klaws, Molecule Man, and Blast Starr. The Court of Evil observes Reed's own memories of the team's battles against Klaws, Molecule Man, and Blast Starr, while the rest of the team escape their confinement. Reed is judged guilty and sentenced to disintegration, but Ben, Johnny and Sue rescue him. The Four then have to face the three super-villains in addition to the planet's evil judge and robot army.

The villainous Impostor poses as the famous director Otto von Lenz after kidnapping the genuine article. He invites the Fantastic Four to star in a film of their own, and they readily accept his offer. He shows them a few highlights of their previous battles against Dr. Doom and the Mole Man as examples of what kind of action he is looking for. Having learnt from the other super-villains' past mistakes, the Impostor instructs the Four to meet him on his private island for the beginning of the film shoot. As they approach in the Fantasticar, the Impostor has his film crew fire a real laser at the craft, forcing the Four to crash-land. On the island, the Impostor challenges the Fantastic Four to evade three challenging traps on the island. The team have to dodge trap after trap and finally confront the Impostor.