When public relations spokesperson Ray Embrey (Jason Bateman) departs from an unsuccessful meeting pitching his All-Heart logo for corporations who are extraordinarily charitable, he becomes trapped on railroad tracks with an incoming freight train. Hancock saves Ray's life, but he causes the train to derail and nearly injures another driver. Hancock is jeered by other drivers for causing more damage, but Ray steps in and thanks Hancock for saving his life. Ray offers to improve Hancock's public image, and Hancock grudgingly accepts. The spokesperson convinces the alcoholic superhero to permit himself to be jailed for outstanding subpoenas so they can show Los Angeles how much the city really needs Hancock. When the crime rate rises after Hancock's incarceration, the superhero is contacted by the Chief of Police. With a new costume from Ray, Hancock intervenes with a bank robbery, rescuing a cop and stopping the leader of the robbers, Red Parker (Eddie Marsan).
After the rescue, Hancock is applauded for handling the bank robbery. The superhero becomes popular once more, as Ray had predicted. He goes out to dinner with Ray and his wife Mary (Charlize Theron), with whom he reveals his apparent immortality and his amnesia from 80 years ago. After Hancock tucks a drunken Ray in bed, he discovers that Mary also has superhuman powers. He threatens to expose her until she explains their origins, and she tells him that they have lived for 3,000 years with their powers, having been called gods and angels in their time. She explains that they are the last of their kind and that their kind are paired. Mary does not tell Hancock the entire truth, and Hancock departs to tell Ray about the conversation. The exchange results in a battle between Hancock and Mary that takes them to downtown Los Angeles, causing significant damage to the area. Ray, downtown in a business meeting, sees and recognizes Mary using abilities like Hancock's.
Hancock is later shot twice in the chest and wounded when he stops a liquor store robbery. After being hospitalized, Mary enters and explains that as the pair of immortals gets close, they begin to lose their powers. She also explains that Hancock was attacked in an alley 80 years prior, where he obtained amnesia. Mary deserted him then in order for him to recover from his injuries. When he is hospitalized, the hospital is raided by Red Parker, the bank robber, and two men that Hancock had humiliated during his incarceration. Mary, visiting Hancock, is shot in the process. Hancock is able to stop two men but is further wounded by them. When Red attempts to finish Hancock off, Ray comes to the rescue and kills the bank robber with a fire axe. With Mary nearly dying, Hancock flees from the hospital so their parting would allow her to heal with her powers. He later winds up in New York City, working as a superhero. As gratitude to Ray, Hancock paints Ray's All-Heart logo on the moon and calls the spokesperson to look up to the worldwide advertisement.