An accidental overdose of gamma radiation creates a mutation in David Banner's DNA, and, whenever he becomes angry, it causes him to metamorphose into a seven foot, 338-pound, green hulking creature. A reporter, Jack McGee, begins investigating claims of a giant monster; his investigation leads to Banner's laboratory. An explosion in the lab kills friend Elaina Marks; McGee, who dubs the creature "the Hulk", believes the Hulk killed David too. Unable to explain the truth, nor control his transformations, David leaves to try and find a cure for himself.

With the world believing him to be dead, David Banner is on the run, trying to find a way to be cured of his transformations into the Hulk. Meanwhile, David lands a job at a ranch, where he befriends a young heiress. He notices that the woman is being given a questionable drug by her physician. He then overhears a plot to kill her so that her stepmother could gain an inheritance; he also learns that the recent death of the young woman's father was no accident. Now, David must get the heiress to safety before it is too late.

David is employed at a scientific firm known as the Joshua-Lambert Institute. He is also happily involved with a colleague named Dr. Maggie Shaw. Two years have passed since his last transformation into the Hulk, and he hopes to rid himself of his alter-ego for good with the Gamma transponder he has created. But before David could be cured of his affliction, a former student of his by the name of Donald Blake makes a surprise visit. Blake, who has discovered that David Banner is still alive, explains to David about his bond with a Viking god named Thor. He calls upon Thor to prove his claim, but unfortunately, things get out of control, and Thor provokes David's transformation into the Hulk. A fight between the Hulk and Thor ensues, leaving the laboratory damaged. To make matters even worse, David and his transponder are soon at risk, thanks to a gang of criminals associated with the Joshua-Lambert Institute.

David finds his way to a large city, unaware that it is run by a crime lord named Wilson Fisk. After two of Fisk's men commit a robbery, one of them attempts to assault a woman. David's intervention leads to a transformation into the Hulk, and the two men flee after being attacked themselves. Although the Hulk saves the woman, he soon changes back to David, who is then wrongfully arrested for the attempted sexual assault, in addition to several other crimes committed by the robbers. Matt Murdock, a blind attorney, is assigned to David's case. Although David is uncooperative, Murdock believes in his innocence, and seeks to prove it. While awaiting trial, David has a nightmare about transforming into the Hulk, and wreaking havoc in the courtroom. This leads to another transformation into the Hulk, who then breaks out of jail.

In a desperate attempt to find a cure, David works as a janitor at a research laboratory in Portland, Oregon. While pretending to be simple-minded, he anonymously guides the genetic research of Dr. Ronald Pratt. After being discovered by Dr. Pratt, David admits to his true identity, and explains his story. Pratt then agrees to help rid him of the Hulk. Unfortunately, however, a group of spies are after Dr. Pratt's research, and want to use it to create "perfect" soldiers.