In 2009, a genetically re-engineered measles virus, originally created as a cure for cancer, turns lethal. The virus kills 90% (5.4 billion out of 6 billion) of the world's population and turns 9.8% (588 million) into vampiric mutants called Darkseekers, who are extremely vulnerable to sunlight, who kill most of the 0.2% (12 million) who were immune to the virus. Three years after the outbreak, US Army virologist Lt Col Robert Neville lives an isolated life in the deserted ruins of Manhattan, unsure if any other uninfected humans are left.
Neville's daily routine includes experimenting on infected rats to find a cure to the virus, searching for food and supplies, and waiting each day for any immune humans who might respond to his continuous recorded radio broadcasts, which instruct them to meet him at midday at the South Street Seaport.
Flashbacks reveal that his wife and daughter died in a helicopter accident during the chaotic evacuation of Manhattan, as the military enforced a quarantine of the island in 2009. Neville stayed behind on the island with other military personnel.
Neville's only companions are his German Shepherd, Samantha (Sam), some mannequins he regularly “talks” with, and the characters on film recordings from video stores. At night, he barricades himself and Sam inside his heavily fortified Washington Square Park home to hide from the Darkseekers.
One day, Sam follows a deer into a building. Neville cautiously goes in after her and finds the deer's corpse along with Sam, but the building is infested by Darkseekers. Both escape unharmed and the attacking Darkseekers are killed by the sunlight.
Neville finds a promising treatment derived from his own blood, so he sets a snare trap and captures a female Darkseeker. A male Darkseeker goes after them, but is blocked by the sunlight and returns to the shadows. Back in his laboratory in the basement of his house, Neville treats the female without success. The next day, he is ensnared in a trap similar to the one he used to capture the female; by the time he escapes, the sun is setting and he is attacked by infected dogs. Neville and Sam eliminate them, but Sam is bitten in the fight. Neville injects her with a strand of his serum, but when she shows signs of infection, Neville strangles her to death. Heartbroken and driven over the edge of insanity, he ventures out and suicidally attacks a group of Darkseekers the next night. He is rescued by a pair of immune humans, Anna and a young boy named Ethan, who have traveled from Maryland after hearing his broadcast. They take the injured Neville back to his home, where Anna explains that they survived the outbreak aboard a Red Cross evacuation ship from São Paulo and are making their way to a survivors' camp in Bethel, Vermont. Neville angrily argues that no such survivors' camp exists.
Neville adjusts the potential cure and injects the female Darkseeker. The next night, a group of Darkseekers, who followed Anna and Neville back the night before, attack the house. Neville, Anna, and Ethan retreat into the basement laboratory, sealing themselves in with the female test subject. Discovering that the last treatment was successful, Neville assesses the situation as a Darkseeker rams himself against a glass door to break in. Neville draws a vial of blood from the woman he cured and gives it to Anna, before shutting her and Ethan inside a coal chute in the back of the lab. He then takes a grenade and kills the Darkseekers at the cost of his own life, saving the cure. The next day, Anna and Ethan arrive at the survivors camp in Bethel. They are greeted by military officers and other survivors, and Anna hands the cure to the officers. Anna narrates that Neville's effort and sacrifice to save humanity ultimately became legend. ReadMore>