In December 2009, military virologist Lieutenant Colonel Robert Neville loses his wife Zoe and daugher Marley in a helicopter accident during the chacotic qurarantine of Manhattan. A genetically-engineered variant of the measles virus created by Dr. Alice Krippin, meant as a cure for cancer, has mutated in to a lethal strain. It quickly spreads through the world, killing 90% of Humanity. By September 2012, Neville is the last remaining human in New York City - and possibly the world - as he looks for survivors in a wasteland ruled by the rest of the plague's survivors who have degenerated into predatory, cannibalistic beings known as Darkseekers.
Robert Neville spends his daily routine looking for survivors and salvaging equipment from other buildings in Manhattan. He also experiments on Infected Rats in hopes of curing the strain, but has been unsuccessful. Each day he sends AM radio broadcasts, hoping to find other survivors, but all of his attempts are unsuccessful. Thus, he comes to believe that he is the last human on earth. His only social outlet is his loyal pet dog Samantha, and interactions with mannequins he has set up as patrons of a video store.
When one of his rat experiments show a promising treatment, Neville sets up a snare trap and captures an Infected Female, brings her to his laboratory, and tries to cure her; once again, his attempts fail. The next day he finds that one of his mannequin friends, whom he called Fred, has been placed in front of Grand Central Terminal. Upon investigation, he is caught in a snare trap (ironically similar to his own) and passes out with Samatha waiting below. Hours later, he is awoken by his watch alerting him to the setting sun. He eventually escapes by cutting the rope with a knife, but in the fall he lands on his own knife, driving the blade into his leg. Both Neville and Samantha try to make it back to Neville's car, but they are attacked by a pack of Infected dogs. Samantha is bitten during the battle, and Neville brings Sam home and injects her with his experimental serum. But it is too late, and as Samantha begins to exhibit the aggressive traits of the Infected, Neville is forced to strangle her, his only companion. Heartbroken, he bitterly sets out towards the pier to kill as many Infected as possible in a Kamikaze battle. He is overwhelmed and nearly killed, but is saved at the last minute by two immune humans named Anna and Ethan. They take him back to his home, where Anna tries to explain that they're on their way to a survivors' camp in Bethel, Vermont. Neville disputes that the camp exists and expresses his doubt when Anna says that God brought her to Neville. the following night the house is attacked by a mob of Darkseekers led by The Alpha Male.
Neville is able to kill many Infected with his traps, but the Darkseekers still manage to enter the house. Robert enters a short confrontation with The Alpha Male, but abandons the fight when he finds Anna and Ethan hiding from another Darkseeker who is tearing a hole through the roof. Neville manages to kill the Darkseeker and the three head for shelter in Neville's laboratory. There, they discover that the female Infected Neville had been experimenting on looks more human and that the serum has worked over time. As the Darkseekers storm the laboratory and the Alpha Male begins assaulting the Plexiglass doors, Neville tries to convince them that he has found a cure, but his pleas fall on deaf ears. He is forced to hide both Anna and Ethan into a safety hatch, along with a blood extract from the Infected containing the cure, before sacrificing himself with a grenade to destroy all the Darkseekers in the room. The scene cuts to Anna and Ethan in their car the following morning, where they come across the survivors' camp. Anna gives a soldier the cure and reflects on Robert Neville's legacy.
As listed in the Credits:
- Robert Neville: Will Smith
- Anna: Alice Braga
- Ethan: Charlie Tahan
- Zoe: Salli Richardson
- Marley: Willow Smith
- Mike (Military Escort): Darrell Foster
- TV Personality: April Grace
- Alpha Male: Dash Mihok
- Alpha Female: Joanna Numata
- Sam: Abbey and Kona
- Jay (Military Driver) Samuel Glen
- Male Evacuee: James McCauley
- Female Evacuee: Marin Ireland
- Sergeant: Pedro Mojica
- Evacuation Cop: Anthona Mazza
- Military Police: Steve Cirbus
- Little Girl Evacuees: Calista Hill, Gabriella Hill, Madeline Hill
- Military Scanning Technician: Adhi Sharma
- Evacuation Cop 2: Tyree Simpson
- Coast Guard Ground Crew: Blake Lange
- Male Evacuee 2: Alexander DiPersia
- Male Evacuee 3: Abraham Sparrow
- President: Patrick Fraley
- Special Blond Model: Caitlin McHugh
- Civilian: Deborah Collins
- Creature Vocals: Mike Patton
- Note:Emma Thompson was supposed to appear in the credits but she didn't, the character was uncredited.
Along with the casual release of I AM LEGEND, A Special edition was also released. It's contents contained a concept art book, six art cards, a collectable lenticular, a digital copy of the film, and the alternate ending of the film, which was considered controversal.