On a sunny day, Rick Jones, listening to music, wanders onto a nuclear testing site unwittingly. Bruce Banner runs out of the bunker and succesfully pushes him into an emergency bunker, though he is caught in the nuclear blast, another scientist caught too when he ran out trying to stop Bruce. The other scientists run out, swatted away through the smoke. A silhouette comes storming out of the smoke, devastating the military personnel before being taken down by a tranquilizer to the neck.
In a quarantine zone, it is found that all the radiation has dissipated in Bruce and he is free to leave, though the other scientist, Samuel Sterns, was left with an inflated brain and green skin. The blast, it had turned out, had made the left side of his brain heavily dominant and inflated it, causing him to become purely logical and objective, with little to no emotion. However, he held a need for vengeance against Bruce, who's stupidity had caused him to be inflicted with this in the first place.
Samuel, having escaped being taken into quarantine, began to formulate his revenge. He attempts to make Bruce look like a public menace by reactivating the Gamma Radiation in him and turning him back into the newly-named "Hulk". However, this fails whenever the Thing of the Fantastic Four takes him down, with the assistance of Leonard Samson. This gives him another plan, though - replicate the events that created the Fantastic Four.
Meanwhile, Leonard Samson attempts to permanently remove the Gamma Radiation from the Hulk, but he only causes himself to become partially irradiated. He isn't nearly as changed as Bruce is, though he still has the ability to change his strength and his hair has turned green. Bruce, having turned into the Hulk mid-experiment, fights him before realising that the two should be allies.
Samuel, now dubbing himself the Leader, has downed a space station containing four participants - Simon Utrecht, corrupt businessman who would do anything for money, including endanger his own life, Michael Steel, who was autistic and dreamed of being superpowered after the Fantastic Four incident, and Ann and James Darnell, who were unaware that the space station would go down and thought they were being hired for a normal job. Utrecht convinces the three that the Hulk had attacked the command center and caused them to crash (though really it was the Leader).
Taking the name of the U Foes, the four attack and defeat the Hulk and Doc Samson. The Fantastic Four intervenes and forces the four to flee, saving the downed duo. Reed informs them that the U Foes have mimicked their abilities and that Utrecht, now going by the name of Vector, is the only truly evil participant. Whenever they next fight the U Foes, Samson is about to use this knowledge, though Michael Steel, now Ironclad, quickly takes him out. The Hulk is more prepared this time and manages to fend them off, whenever Rick Jones arrives and tells them that the Hulk isn't evil. When Ann, James, and Michael are about to question this, Vector knocks him away with ease, angering the Hulk.
Rick returns while the Hulk has the U Foes distracted, awakening Samson, who tells them the whole story. The other three turn on Vector, but the Leader arrives in a mech. The Hulk takes it down in battle, though, and the U Foes become a superhero team while the Leader is turned into the US Military.
In the stinger of the movie, we see Jennifer Walters getting a blood transfusion. The blood bag is labelled "BRUCE BANNER". It's mentioned that he is her cousin, and when the blood begins to enter her veins, they turn green.