In December 2020, famous actor Arthur Leander dies on stage during a Chicago production of King Lear. Audience member Jeevan Chaudhary, who attempts to help despite his inexperience, accompanies abandoned child actor Kirsten Raymonde home. On the way, Jeevan receives a call from his doctor sister Siya warning that a deadly virus has come from Asia into America. Unable to contact Kirsten's parents at her home, Jeevan and Kirsten are forced to buy several grocery carts' worth of food and barricade themselves inside the apartment of Jeevan's brother Frank, a writer. From his windows, they watch a plane fall from the sky and crash. Eighty days later, Jeevan and Kirsten leave the apartment to a snowy wasteland filled with abandoned cars, humanity having been decimated by the flu pandemic. Twenty years later, adult Kirsten rehearses a play while reading a copy of a graphic novel called Station Eleven that had once been given to Arthur Leander.

Two years after the outbreak of the virus, a lone Kirsten comes across a composer named Sarah who leads and performs for the Travelling Symphony, a nomadic group of actors and musicians who perform William Shakespeare plays on a defined tour path called the "Wheel"; Sarah invites Kirsten to join. Kirsten grows up to become the Symphony's star actress. Arriving at Lake Michigan, Kirsten and fellow actor Alex, who was born after the pandemic, meet a suspicious man, David, and supposedly his teenage son Cody. They lie about their origins and David quotes Station Eleven, which Kirsten believes only she has read due to her having the only copy. Kirsten also finds hook-shaped symbols in the woods that reference Station Eleven's illustrations, and becomes wary; Alex, however, sympathizes with the two. The Symphony puts on Hamlet, during which Kirsten flashes back to the outset of the virus, when she, Jeevan, and Frank learn her parents are deceased via text message. After the play, an emissary from a secret community called the Museum of Civilization approaches Sarah to perform there, but she refuses to stray from the Wheel. Kirsten confronts David about the book, and after he threatens that the Symphony members will "disappear" if they don't give him refuge, she stabs him; he goes on to reference a prophecy and further quotes from Station Eleven. The next morning, Kirsten finds that Cody has taken David and fled, the latter having survived and painted the hook symbol with his blood.

One year after the pandemic sets in, Jeevan and Kirsten are living alone in a cabin. One day, Station Eleven goes missing, resulting in an argument between the two. Jeevan eventually leaves to go find it, but Kirsten finds it outside the next morning and Jeevan nowhere to be found. In the present, Kirsten warns Alex to be wary of outsiders such as David, but Alex rebuffs her and claims that anyone born before the pandemic is unnecessarily cautious. After again rebuffing the man from the Museum of Civilization, the Symphony comes upon a fork in the road. The Symphony used to split the group between musicians and actors to travel to a performance town and a country club called Pingtree respectively, but stopped the practice when Sarah's ex-husband and the Symphony's former director, Gil, settled down with his new wife in Pingtree; they now run a community of professors. While preparing to head to the performance town, Alex finds a note that reads "beware of the Prophet" (David), who runs a cult of children by preying on their naivete to claim there was never a pandemic and abducting them from various towns. Alex shows this to Kirsten, who reveals she hid Station Eleven in Pingtree. In order to check in on the book, Kirsten tricks Sarah into splitting the Symphony to visit Pingtree. When they arrive, they discover the Prophet has already taken all the children of their community. In order to alleviate the professors' pain, Sarah decides to perform a modern adaptation of Hamlet for them, with Alex in her first leading role. While the Symphony rehearses, Kirsten recovers Station Eleven, which she had hidden in Gil's office. Meeting with Gil, Kirsten requests he rejoin the Symphony, but he refuses. The play is a success, but Alex leaves on horseback after a fight with Kirsten, which mirrors the fight Kirsten had with Jeevan. As Kirsten prepares to look for her, she encounters one of the children, who is wearing a mine that Gil set after the Prophet's attack as an explosive belt. Kirsten chases the child, but she rendezvouses with another child that is meeting with Gil. While quoting Station Eleven, the two children hug Gil, setting off the mines and killing all three of them, though Kirsten survives the blast.

Kirsten and The Prophet continue on their way to Severn City Airport, where the rest of the Travelling Symphony are being held in quarantine prior to their performance. After Miles finds the duo out in the woods, Clark welcomes Kirsten and The Prophet to the airport community, but has them perform a scene from a play to prove they are actors. The duo improvise a sequence from Station Eleven. Afterwards, Kirsten reunites with the Travelling Symphony, but is devastated to learn Sarah has suffered a heart attack and no one has seen her since. Kirsten discovers the Prophet's connection to the Museum of Civilization and the Station Eleven graphic novel. The Prophet is reunited with Clark and Elizabeth, but refuses to acknowledge them as he sets fire to the Museum of Civilization. Sarah makes Kirsten promise to not tell the troupe of her death until after the play. Prior to the outbreak, Arthur takes the sober Clark on a bender. They fight over their divergent paths in life, Clark having failed at acting and turned to business, and over Miranda. The next morning, Clark insults Arthur's parenting before realizing Tyler and Elizabeth were there.