Emotionally stunted Dr. Bruce Banner (Eric Bana) is part of a research team at the University of California at Berkeley. Corporate hustler Glenn Talbot (Josh Lucas) takes notice of the lab and makes plans to take it over. Then Bruce accidentally gets hit by an experimental ray and grows into a huge beast, destroying the lab in the process.

A creepy janitor who claims to be his real father, Dr. David Banner (Nick Nolte), starts to secretly use the experimental ray on himself. He creates some mutant dogs and sends them after Bruce's lab mate and ex-girlfriend Betty Ross (Jennifer Connelly). After Bruce saves her life in the form of the Hulk, she lets her distant father, General Ross (Sam Elliott), take him to an abandoned army base in the desert. However, Glenn Talbot takes over the operation and wants to patent the creature's superpowers for his own profit, so he holds Bruce unconscious in an isolation tank.

When provoked, Bruce turns into the Hulk and makes a break for San Francisco, leading to a desert chase sequence involving military aircraft, tanks, and bombs. Only the sight of Betty can make him turn back to his human form. When he is eventually captured, Dr. David Banner shows up for a final confrontation with his son and his old adversary, General Ross.