Scientist David Banner introduces the idea of creating super soldiers by introducing modified DNA sequences extracted from various animals to strengthen the human cellular response, making them effectively impervious to any weaponized agent, but General Thaddeus Ross denies him permission to use human subjects. Banner subsequently conducts the experiments on himself. After the birth of his son Bruce, he finds that his son may have inherited the effects and seeks a cure, but is stopped in the process. Bruce remembers nothing of the incident after a traumatic event, and has been raised by the Krenslers. Years later, Bruce is a geneticist working with his ex-girlfriend Betty Ross, within the Berkeley Biotechnology Institute on nanomed research. The pair hope to achieve instantenous cell repair by using low level Gamma radiation exposure to activate the nanomeds once they are introduced into a living organism. During routine maintenance of their appropriated Gammaspectrometer, a circuit shorts and triggers the experiment's program sequence. Unable to prevent the machine from firing, Bruce throws himself in front of his colleague to shield him and is exposed to incredibly toxic levels of Gamma.
Betty visits Bruce in the hospital and remarks that he should be dead, but Bruce feels great. A new janitor at the lab claims that he is Bruce's biological father, of whom Bruce has no recollection. When under extreme stress, Bruce transforms into the Hulk who destroys the laboratory, though he has no memory of the incident. General Ross suspects Bruce of collaborating with his father but then deduces Bruce has repressed memories. He orders Bruce to be put under house arrest. Through a phone call with his father, Bruce learns that the radiation unleashed something that was already in his DNA, and that David Banner plans to have Betty killed by his dogs, which now have similar powers to the Hulk (thanks to David mutating them with gamma radiation), and he is attacked by Major Glenn Talbot, leading to a transformation into the Hulk. The Hulk seriously injures Talbot before leaping to save Betty from the dogs. The Hulk kills David's dogs and changes back into Bruce before being captured by the military the next morning.
Kept at a secret desert base, Bruce is kept under observation while Talbot intends to weaponize the Hulk's powers. David Banner tries to recreate Bruce's failed experiment, but instead of turning into another Hulk he finds himself able to absorb any materials and energy he touches, and hands himself over to the military after telling Betty that he murdered his wife in front of the child Bruce. Bruce has a nightmare about the event which leads to a more powerful transformation of the Hulk. Talbot is killed in an explosion of his own making. The Hulk escapes the base and rampages his way across the desert to San Francisco, battling army forces sent after him. When Betty calms him into his human form, General Ross realizes that the Hulk cannot be controlled and that Bruce should be executed.
At their mutual execution, David Banner tries to taunt his son into transforming into Hulk, but fails. He then decides to "go first" and bites an electrical cable absorbing all the electricity in San Francisco. The electricity hits Bruce, triggering his own transformation. A brutal fight ensues between David and the Hulk, with David absorbing Hulk's energy during the fight. David finds that the Hulk's energy is too much for him to handle and he is killed by an army missile at the height of his weakness. One year later, though Bruce is presumed dead, General Ross mentions apparent Hulk sightings and Betty admits her love for Bruce. In a South American jungle, Bruce has become a doctor and is approached by rebel militants who want to take medical supplies from the poor. Bruce's eyes turn green and a scream of the Hulk is heard.