In 2009, a genetically re-engineered measles virus, originally created as a cure for cancer, turns into a lethal strain which kills 94% of those it infects, mutates 5% into predatory, nocturnal and vampiric mutants, who are extremely vulnerable to sunlight, with only 1% immune. Three years after the outbreak, US Army virologist Lieutenant Colonel Robert Neville (Will Smith) lives an isolated life in the deserted ruins of New York City, unsure if any other uninfected humans are left in the world.
Neville's daily routine includes experimentation on infected rats to find a cure to the virus and venturing through Manhattan to search for food and supplies. Also awaiting for potential human survivors each day for a response to his continuous recorded radio broadcasts, which instruct any uninfected survivors to meet him at midday at the South Street Seaport.