While watching a production of King Lear at the Elgin Theatre in Toronto, Jeevan watches as the actor playing Lear, Arthur Leander, has a heart attack. Since he has begun training as a paramedic, Jeevan tries to resuscitate Arthur but is unsuccessful. Instead he comforts one of the child actors in the production, Kirsten. After leaving the play Jeevan goes for a walk in the snow and receives a call from one of his doctor friends. This friend warns him to get out of the city as a mysterious Georgia flu is spreading rapidly and will soon become a full out epidemic. Jeevan loads up on supplies and goes to stay with his brother. We find out that many of the actors, actresses and others that had gathered to mourn Arthur's death die within three weeks of the beginning epidemic.
Twenty years later Kirsten Raymonde is part of a nomadic group of actors and musicians known as the Travelling Symphony. Kirsten, who was eight at the time of the plague, can remember little of her life before Year Zero but clings to a two volume set of graphic novels given to her by Arthur before his death called Dr. Eleven. The troupe operates on a two-year cycle orbiting around the Great Lakes region and during this time Kirsten scavenges abandoned homes looking for old tabloid magazines for traces of Arthur. After returning to a small town where they left their pregnant friend, Charlie, and her husband, Jeremy, the troupe is disturbed to find that not only are their friends missing but the town is under the control of the mysterious Prophet, who rapes young girls that he claims as his "wives". The troupe quickly leaves and is determined to go off route to the Museum of Civilization, which is actually a former airport, where they believe they might find their missing friends. However, en route they discover a young stowaway who left the town as she was promised to the Prophet as his bride. Shortly after, members of the troupe begin to disappear until finally the entire troupe is gone leaving only Kirsten and her friend August. Frightened, they continue on to the Museum hoping to be reunited with others.
Unbeknownst to Kirsten the graphic novel Dr. Eleven was written by Arthur's first wife, Miranda. Fourteen years before the collapse of civilization Miranda left an abusive relationship with an artist and married Arthur. However as Arthur's fame hit its peak Miranda realized he was having an affair with a blonde woman who would become his second wife, Elizabeth. The night that Miranda discovers the affair she walks out of her home and asks the paparazzo outside if he has a cigarette. The paparazzo turns out be Jeevan. Years later, when Jeevan is trying to reinvent himself as an entertainment journalist Arthur gives him the exclusive that he is leaving Elizabeth and his young child to be with his co-star of his new movie Lydia Marks. Jeevan reflects on this while he and his brother Frank are locked in Frank's apartment waiting for the epidemic to run its course. After a while they realize that no one is coming to save them. Frank, a paraplegic, commits suicide in order to allow his brother to move freely. Jeevan embarks on a journey south and eventually finds a new settlement where he marries and becomes the town doctor.
Meanwhile, back in Year Zero, Clark, one of Arthur's friends, is the one who informs Elizabeth that Arthur is dead. Clark, Elizabeth and Elizabeth's son, Tyler, happen to be on the same flight from New York to Toronto to go to Arthur's funeral when it is redirected to the fictional Severn City Airport due to the epidemic. Clark ends up resettling in the airport post-pandemic and becomes the "curator" of the Museum of Civilization where he gathers artifacts such as iPhones and laptops and explains to children born post-pandemic what they did. While most of the airport survivors manage to eke out an existence and cope with their new life Elizabeth and Tyler grow increasingly religious and strange, believing that the epidemic happened for a reason and spared those who were good. They finally leave in Year Two with a religious cult.
Back in Year Twenty Kirsten and August meet a group of the Prophet's men along with Sayid, one of the members of their troupe. They manage to kill the men and free Sayid who informs them that one of their friends, Dieter, was killed and that the hostage that the Prophet's men took to replace Dieter managed to escape and warn the troupe, explaining how Kirsten and August were unable to find them. Frightened, Kirsten, August and Sayid try to hurry towards the Severn City Airport. Kirsten however is discovered by the Prophet himself, whose dog she realizes has the same name as Dr. Eleven's in the Dr. Eleven comics. Just before the Prophet is about to kill her he speaks some lines that she recognizes from Dr. Eleven. She quotes some back to him, distracting him long enough that one of his younger sentries, who does not want to be a part of his cult, shoots and kills the Prophet before taking his own life. Kirsten and the rest continue on to the Museum of Civilization where they are reunited with Charlie, Jeremy and the rest of the troupe. Clark, who has stayed at the museum for twenty years, realizes who Kirsten is, her attachment to Arthur, and that the Prophet is the grown up Tyler. Furthermore, he shows Kirsten from the watch tower of the airport there is a town to the south that uses electricity, showing that civilization is beginning to take root again.
Five weeks later Kirsten leaves with the theatre troupe for the south. She leaves one volume of Dr. Eleven with Clark who begins to read it and recognizes a scene in the graphic novel that is borrowed from a dinner party which he, Arthur and Miranda once attended.