Plot

Near the end of the 1960s, scientist David Banner (Nick Nolte) is conducting genetics research and is attempting to mutate human DNA to boost the immune systems of soldiers to help them heal quickly in battle. After he is denied permission to conduct human trials, Banner experiments on himself. As time passes, David realizes his mutant DNA has been passed on to his son and attempts to find a cure. The military, led by Thunderbolt Ross, shuts down Banner's research after discovering his unauthorized and dangerous experiments. In a fit of rage, Banner triggers a massive gamma explosion, releasing tons of radioactive material and speeds back home to kill his son with a cook's knife in order to prevent him from turning into a monster, but accidentally fatally stabs his wife when she tries to stop him. David is arrested and imprisoned at a mental hospital for 26 years while young Bruce is adopted into a foster home, growing up to believe his parents are both dead. A few years later after the explosion, Bruce's hometown is abandoned and evacuated.

In 2003, Bruce Banner (Eric Bana) is now a researcher at the University of California, Berkeley. The military takes an interest in Banner's research into Nanomeds and sends Major Talbot (Josh Lucas) to investigate it. Meanwhile, David Banner reappears and begins to infiltrate Bruce's life, taking a job as a janitor at the lab and secretly keeping an eye on Bruce. Thunderbolt Ross (Sam Elliott) is informed of the research and becomes concerned for his daughter Betty (Jennifer Connelly), who works at the lab with Bruce. Ross meets with Betty and informs her of his concerns, but she becomes angry that he came there for business and not to reconcile with her.

In a lab computer glitch, Bruce is accidentally exposed to gamma radiation and the Nanomeds, which combine with his already mutated DNA and protect him from being killed by the radiation. After the accident, Bruce awakens in a hospital bed and Betty informs him that he should be dead, but instead, he is better than he was before. That night, David finally confronts Bruce and reveals himself as Bruce's father. He tells Bruce to watch his temper, and quietly steals some of Bruce's hair to conduct his own tests on. David begins using Bruce's altered DNA in animal testing, producing a pack of mutated dogs.

The combined frustration and stress around Bruce begin to overwhelm him and he transforms into the Hulk, destroying the lab and rampaging around, ripping all the equipment and furniture to pieces. The next day, Betty finds Bruce passed out at home. As he is trying to piece together what happened, General Ross arrives and places him under house arrest. Betty tracks down David and confronts him, prompting David to call Bruce and tell him that he has unleashed three enormous mutant dogs to track down and kill Betty. Bruce is further provoked by Major Talbot and transforms into Hulk. seriously injuring Major Talbot by breaking his neck, arm, and right leg before rushing to save Betty and ripping the dogs apart. The next morning, Bruce is tranquilized by Ross and taken to a deep underground Arizona desert base where Major Talbot is in charge of research. Betty wants to help Bruce control his transformations, but General Ross believes that Bruce is a danger who is doomed to follow in his father's footsteps.

Major Talbot sees an opportunity to profit from the Hulk's strength and regenerative capability. Then he tortures Bruce trying to get a sample off him, but he refuses. He puts Bruce in a sensory deprivation tank and triggers a transformation into the Hulk, who escapes from the research facility, damaging some of the equipment and destroying the control center in the process. Talbot is killed when a gun he fires at the Hulk ricochets back on him.

The escaped Hulk flees into the desert, battling the army forces sent after him. He discovers that he can cover great distances by leaping with his powerful legs and uses this ability to quickly make his way to San Francisco to find Betty. While on his journey, General Ross sends 4 helicopters and 4 tanks to track and restrain him, but they all get destroyed. Betty defies her father and confronts the Hulk, who is soothed by her appearance and transforms back into Bruce Banner. Meanwhile, David breaks into the lab and uses Bruce's Nanomed technology on himself, gaining the ability to meld with and absorb the properties of any substance he touches. He goes to Betty's house and offers to turn himself in, with the condition that he can see Bruce one more time.

General Ross agrees and allows David to talk to Bruce. David tells Bruce that he wants to see his real son, the Hulk. Bruce refuses to transform and David grabs a nearby power wire, mutating into a large power-absorbing monster. Bruce becomes the Hulk and the two fly to a forest and battle. The two fight each other to a lake, where David freezes the Hulk in the water and taunts him, trying to get Bruce to release his power. Finally, Bruce unleashes the full power of the Hulk, which overwhelms his father and causes him to swell into a huge, unstable mushroom-shaped form.

At the same time, General Ross detonates a gamma bomb on them. David is destroyed, but Bruce (who is unconscious at the bottom of the lake) survives and remembers David tucking him into bed as a child saying sweet dreams which probably means his father still might have loved him. One year later, Bruce is shown working as a doctor in a rainforest. Some soldiers try to steal some medical supplies from the camp, and Bruce confronts them, telling them "Don't make me angry! You wouldn't like me when I'm angry!". Banner's eyes turn green as the camera zooms out and the loud roar of the Hulk can be heard as the screen fades to green.