During a production of King Lear at the Elgin Theatre in Toronto, aspiring paramedic Jeevan Chaudhary watches as the actor playing Lear, Arthur Leander, has a heart attack. Jeevan tries to resuscitate Arthur, but is unsuccessful. Instead, Jeevan comforts one of the child actors in the production, Kirsten Raymonde. After leaving the play, Jeevan goes for a walk in the snow and receives a call from his old friend who is a doctor in Toronto. He warns Jeevan to get out of the city, as the mysterious and deadly Georgia Flu is spreading rapidly and will soon become a full-blown pandemic. Jeevan loads up on supplies and goes to stay with his brother Frank. Many of the actors, actresses, and others that had gathered to mourn Arthur's death die within the next three weeks.
Twenty years later, Kirsten is part of a nomadic group of actors and musicians known as the Travelling Symphony. Kirsten, who was eight at the time of the outbreak, 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, titled Station Eleven. The troupe operates on a two-year cycle touring the Great Lakes region, performing Shakespeare plays and classical music, while Kirsten scavenges abandoned homes for props, costumes, and traces of Arthur in tabloid magazines.
The troupe intends to reunite with two members they left behind – the pregnant Charlie, and her husband, Jeremy – at a small town. Upon arriving, they are disturbed to find that their friends are missing, and that the town is now under the control of the Prophet, who rapes several young girls he claims as his "wives". The troupe quickly leaves, and goes off-route to the Museum of Civilization, a settlement where they believe they might find their missing friends. En route, they discover a young stowaway who fled the town, as she was promised to the Prophet as his next 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Unbeknownst to Kirsten, Station Eleven is an unpublished passion project by Arthur's first wife Miranda. Fourteen years before the collapse of civilization, Miranda left an abusive boyfriend and married Arthur, a friend from her hometown in coastal British Columbia who has since become a famous actor. As Arthur's fame hit its peak, Miranda realized he was having an affair with the woman who would become his second wife, Elizabeth. The night that Miranda discovers the affair, she walks out of her home and asks a paparazzo outside if he has a cigarette; the paparazzo is Jeevan. Years later, when Jeevan is trying to reinvent himself as an entertainment journalist, Arthur gives him an exclusive interview; Arthur tells Jeevan that he is leaving Elizabeth and their young son Tyler to be with another woman. Jeevan reflects on this while he and Frank are quarantining in Frank's apartment. After many weeks, they realize that no one is coming to save them. Frank, who is paraplegic, kills himself to spare Jeevan from feeling responsible for him. Jeevan embarks on a journey south, and after many years, finds a new settlement in Virginia, where he marries and becomes the town doctor.
In Year Zero, Arthur's best friend, Clark, informs Elizabeth that Arthur is dead. Clark, Elizabeth, and Tyler happen to board the same flight from New York City to Toronto to attend Arthur's funeral, but it is grounded at the Severn City Airport due to the pandemic. The passengers, having nowhere to go, create a settlement in the airport, and Clark becomes the "curator" of the Museum of Civilization, where he gathers artifacts such as iPhones and laptop computers. While most of the airport survivors adapt to their new life, Elizabeth and Tyler embrace religious zealotry, believing that the pandemic happened for a reason and spared those who were good. After two years, they leave with a religious cult.
In the present, Kirsten and August find a group of the Prophet's men holding Sayid, a member of their troupe, hostage. They kill the men and free Sayid, who explains that their friend Dieter was killed, while another hostage escaped, warned the troupe, and sent them on another road; this explains how the rest of the Symphony went missing. The trio leave for the Severn City Airport, but Kirsten is soon discovered by the Prophet. Just before he is about to kill her, he refers to the "Undersea," a place from the Station Eleven comics. Kirsten quotes lines from Station Eleven, distracting the Prophet long enough that a younger sentry, having a crisis of faith, shoots and kills him, before taking his own life. The trio continues to the Museum of Civilization, where they are reunited with Charlie, Jeremy, and the rest of the troupe. Clark, who has lived in the museum for twenty years, realizes who Kirsten is, her attachment to Arthur, and that the Prophet was Tyler Leander. Clark takes Kirsten up to the control tower of the airport, where he shows her there is a town with lights, suggesting civilization is beginning to take root again.
Five weeks later, Kirsten leaves with the Travelling Symphony for the town. She gives one copy of Station Eleven to Clark's museum. He begins to read it and recognizes a scene that is borrowed from a dinner party which he, Arthur, and Miranda once attended.
