Near the close of the 1960s, scientist David Banner (played by Nick Nolte) is on a quest to revolutionize genetics through his research aimed at enhancing the immune systems of soldiers, hoping to enable quicker recovery in combat situations. After being denied the necessary permissions to conduct human trials, he decides to experiment on himself. As time progresses, David discovers that his mutated DNA has been transferred to his son, prompting him to seek a cure. However, the military, led by Thunderbolt Ross (Sam Elliott), intervenes and halts David's dangerous research once they uncover his unauthorized activities.
In a desperate moment fueled by rage, David triggers a catastrophic gamma explosion, releasing a significant amount of radioactive material. In a chaotic attempt to protect his son, he rushes home with the intention of killing him to prevent him from becoming a monster. In a tragic turn of events, he fatally stabs his wife during a confrontation. Subsequently, David is incarcerated in a mental institution for 26 years, while young Bruce remains in foster care, raised to believe both his parents have perished. A few years post-explosion, Bruce's hometown lies desolate and abandoned.
Fast forward to 2003, Bruce Banner (Eric Bana) finds himself as a researcher at the University of California, Berkeley. The military takes an interest in his work surrounding Nanomeds and assigns Major Talbot (Josh Lucas) to observe him. Unbeknownst to Bruce, his estranged father, David, has re-emerged, infiltrating Bruce's life under the guise of a janitor at the lab, while secretly surveilling his son. Concerned for his daughter, Betty (Jennifer Connelly), who works alongside Bruce, Thunderbolt Ross expresses his worries to her, but Betty retaliates, accusing him of prioritizing work over their relationship.
A lab mishap results in Bruce being exposed to gamma radiation, which, combined with the Nanomeds, fortuitously saves him from death and enhances his abilities. Awakening in a hospital, he learns from Betty that he should be dead but is instead stronger than before. That night, David confronts his son and discloses his identity as Bruce's father, cryptically warning him to control his temper while covertly taking some of Bruce's hair for his own experiments. David conducts tests on animals that result in a group of viciously mutated dogs.
Bruce's mounting stress culminates in a transformation into the Hulk, as he wreaks havoc in the lab, obliterating everything in sight. The following day, Betty finds him unconscious at home, and as he seeks to understand the chaos, General Ross places him under house arrest. In the meantime, Betty tracks down David, confronting him. Angered, David informs Bruce that he has unleashed three monstrous dogs to hunt down Betty. This provocation incites Bruce’s transformation, where the Hulk injures Major Talbot before racing to rescue Betty and dismantles the dogs.
Bruce is subsequently tranquilized by Ross and taken to a secret military facility in the Arizona desert, overseen by Major Talbot. Despite Betty’s desire to help Bruce control his transformations, General Ross believes Bruce poses a significant threat, fearing he may follow in David's destructive footsteps. Talbot sees a chance for military gain from the Hulk’s powers, tormenting Bruce for samples. He triggers another transformation, causing the Hulk to escape and demolish the facility in the process, resulting in Talbot's accidental death.
The Hulk escapes into the wilderness, engaging in a cat-and-mouse chase with military forces. As Bruce discovers his leaping abilities, he aims for San Francisco to seek out Betty. Despite General Ross sending a fleet of helicopters and tanks, they are powerless against the Hulk's might. Betty bravely confronts the creature, calming him, which allows him to revert to Bruce.
Meanwhile, David breaks into the lab, using Bruce's technology to gain new abilities, and requests to see Bruce one last time, which Ross begrudgingly permits. During their meeting, David insists he wishes to see his true son—the Hulk. When Bruce refuses to transform, David retaliates by absorbing a power wire, morphing into a colossal, unstable monster. This provokes Bruce, who becomes the Hulk, leading them to a fierce confrontation in the forest.
Their battle extends to a lake, where David attempts to taunt Bruce into unleashing his full might. Ultimately, Bruce reveals the true power of the Hulk, overcoming David, who is forced into a grotesque and unstable form. As General Ross detonates a gamma bomb to eliminate the threat, David is obliterated, while Bruce, unconscious beneath the lake, recalls a tender moment from his childhood when David tucked him in, hinting at a flicker of paternal love.
One year later, Bruce, now a doctor in a distant rainforest, faces a new challenge when soldiers try to seize medical supplies from his camp. He warns them, “Don’t make me angry! You wouldn’t like me when I’m angry!” As the camera zooms out, Bruce’s eyes glimmer green, and the chilling roar of the Hulk echoes as the scene fades to green.
