John Hancock (Will Smith) is a well-known vigilante who lives in Los Angeles and has powers of a superhero such as being very strong, invulnerable and being able to fly. He regularly saves lives and catches criminals. However, Hancock's reckless actions routinely cost the city millions of dollars, as Hancock is nearly always drunk while attempting to capture criminals. Hancock, however, does not care what the city thinks, and routinely ignores subpoenas and talks rudely to strangers.

One day, Hancock saves Ray Embrey (Jason Bateman), a public-relations spokesperson whose attempts to market his world-changing "All-Heart" charity aren't gaining traction, from being run over by a train (in the process causing a massive derailment in Hancock's haphazard manner). Ray feels he owes Hancock his life, and he makes it his mission to change Hancock's public image for the better.

Ray teaches Hancock to make the compliment "Good job!" to the police. He also supplies him with a costume, after some other models are rejected by Hancock as being homo Ray also persuades Hancock to give himself in and accept going to prison so that the public will realize how much they need him; he argues that in the worst case he can always break out. He reluctantly agrees and after a month the Chief of Police calls him to help save a female officer who is pinned down in a chaotic bank robbery shootout. After emphatically asking her permission to touch her, explaining that it is not sexual, Hancock saves the officer, removes the gang, and cuts the hand off the gang's leader Kenneth "Red" Parker Jr. (Eddie Marsan), who is holding a dead man's switch on a detonator.

After the rescue, Hancock becomes popular once more, as Ray had predicted. Ray and his wife Mary (Charlize Theron) go out to dinner with Hancock, where he relates how he woke up 80 years earlier with no memories of his life. Later that night, while Ray sleeps after passing out from drinking too much, Hancock discovers that Mary has super powers as well. Mary reveals that they are the last two "gods" or "angels" and have been a couple off and on for 3,000 years. All the others of their kind died - when they get too close to each other they become mortal, which allows them to be injured, and age. These immortals were created in pairs, and are inevitably drawn towards each other; she is Hancock's other half and wife for the last three millenia. She left him after he lost his memory after an attack in order to keep him from becoming mortal.

Mary and Hancock have a brief fight over revealing this fact to Ray, inadvertently doing just that in the process. Hancock is shot twice in the chest when he stops a liquor store robbery. When he is admitted to the hospital, the news media covers it, thus revealing his location. Shortly before this the news had also revealed Parker had orchestrated a jail break during which eight men escape. Along with two other men, whom Hancock attacked and humiliated during his first day in prison, the revenge-driven villain heads to the hospital. Mary is shot while attempting to protect Hancock. Hancock finishes off the henchmen, but is still severely wounded. Just as he is about to be killed by Parker, Ray grabs a fire axe and chops the killer's other hand off and striking him on the chest with it, thus saving Hancock. Hancock leaves the hospital, Mary is saved and Hancock's powers are fully restored. The film ends with Hancock accepting his role as a hero and living in New York City, letting Ray and Mary live a normal life while remaining their friend. He calls them on the phone one evening as they walk along the Santa Monica Pier and has them look up to the sky. He has painted Ray's All-Heart logo on the moon as a thanks. The movie ends with a middle after credit spoiler showing Hancock fighting crime in New York City.