In 2012, humanity was ultimately brought down by a virus. Robert Neville (played by Will Smith), a former military virologist, survived as the only human in New York City due to his natural antibodies preventing infection. He even once believed he was the sole survivor of humanity worldwide.

The film tells the story of Constantine, who has had the ability to perceive demons and angels since childhood. This supernatural ability causes endless troubles for him, leading him to contemplate suicide. However, both heaven and hell refuse to accept Constantine. Losing faith in humanity, demons, and even angels, he wanders between heaven, hell, and the mortal realm.