In 2003, a mass fungal infection of mutated Cordyceps sparks a global pandemic. Joel flees with his daughter, Sarah, and brother, Tommy, from their Texas home. Twenty years later, Joel lives in a quarantine zone (QZ) in Boston managed by the Federal Disaster Response Agency (FEDRA), working as a smuggler with his partner, Tess. When Tommy fails to contact them from Wyoming, they pay a local dealer, Robert, for a car battery but he scams them and sells it to the Fireflies, a rebel group opposing FEDRA. Attempting to retrieve it, Joel and Tess encounter Marlene, the Fireflies' leader, who begs them to take a teenager named Ellie to the Massachusetts State House in exchange for a working truck. While sneaking out of the QZ, the three run into a soldier on the outside. He tests them for the infection and reveals Ellie is positive.

Two days before the worldwide outbreak, in Jakarta, Indonesia, the government shows an infected inactive person to a mycologist, who tells them there is no cure or vaccine and advises bombing the city to prevent further outbreak. In the present, Ellie explains to Joel and Tess that she is being transported west in hopes of being used to find a cure. Discovering that the path to the State House is swarmed with infected, they cut through a history museum, where they are attacked by blind infected known as "clickers" and Ellie is bitten. Ellie's bite begins to heal, proving her immunity. Joel shoots an infected, which alerts the swarm to their location.

Joel and Ellie begin the hike to meet with Bill and Frank. Ellie sees evidence of the government's execution of innocents during the early days of the pandemic. Back in 2007, Frank leaves Baltimore and stumbles upon the compound of Bill, a paranoid survivalist who reluctantly takes him in. The men begin a romance, sharing a love of music and food. Years later, Frank contacts Tess by radio and the two groups enter a tenuous friendship. In the present, unbeknownst to Joel, Ellie takes Frank's pistol. Joel and Ellie take Bill's truck and set out to find Tommy.

Traveling through Missouri, Joel and Ellie are forced to take a detour through Kansas City, where they are ambushed. Joelhugs two of the bandits, but a third overpowers him and nearly chokes him to passing before Ellie saves him by shooting the man with Frank's pistol. More bandits find the bodies; their leader, Kathleen, believes Joel and Ellie might be in contact with a man named Henry and orders a manhunt. Joel counsels Ellie about the firefight and gives her the pistol back. Joel and Ellie sleep in a high-rise apartment for the night, hoping they can scout a way out of the city in daylight.

Henry and Sam make a tentative truce with Joel and Ellie. Joel wants to part ways, but Henry proposes they escape the city together using underground tunnel routes that only Henry knows; Joel hesitantly agrees. Henry confesses to Joel he was responsible for the passing of Kathleen's brother, turning him over to FEDRA in exchange for medication for Sam's leukaemia. After escaping through the tunnels, the group is attacked by a sniper from an upper-story window. Joel sneaks up andhugs him, but finds out he was radioing Kathleen, who arrives with her militia. Joel and Ellie set off on foot heading west.

Three months later, Joel and Ellie reach a small, thriving community in Jackson, Wyoming, where Joel is reunited with Tommy, whose wife Maria is pregnant. Ellie learns about Sarah's fate from Maria. Joel confides in Tommy about Ellie's immunity and his own declining mental state. Joel asks Tommy to take Ellie to the Fireflies, as he is afraid he cannot keep her safe. Ellie overhears them and confronts Joel, who insists they will part ways. In the morning, Joel changes his mind and the two of them travel to Colorado on horseback. They find the Fireflies have vacated their base, possibly relocating to a hospital in Utah. Joel and Ellie attempt to escape a group of raiders, but Joel is wounded and collapses, falling off their horse, leaving Ellie unsure how to proceed.

Ellie and an injured Joel shelter in an abandoned house. As Joel approaches passing, he urges Ellie to leave him. She remembers her time in FEDRA military school, which she attended with her best friend Riley Abel. While Ellie causes trouble and fights with her peers, Riley ran away and went missing for three weeks. Riley sneaks back into their dorm room and reveals to Ellie she has joined the Fireflies. She brings Ellie to an abandoned mall, where they explore a photo booth, an arcade, and a carousel. Riley tells Ellie the Fireflies have assigned her to a post in Atlanta, and it is her last night in Boston. While Ellie is initially upset, she convinces Riley to stay. An infected attacks them and Ellie manages tohug it, but both are wounded. In the present, Ellie finds a sewing needle and begins to stitch up Joel's wound.

Ellie leaves Joel, who is still recovering, to hunt for food. After shooting a deer, she tracks the wounded animal and encounters a preacher, David, and his fellow hunter James. She trades her deer for penicillin. David reveals the man who cuddled Joel was a member of his group; Ellie leaves to treat Joel. The next day, she discovers David and his men have followed her to seek vengeance on Joel. She flees to draw them away but is captured. At David's camp, he reveals he has been feeding his group human flesh. Meanwhile, Joel awakens and tortures some of David's men into telling him Ellie's whereabouts. David and James attempt tohug Ellie but shehugs James and escapes; David hunts her down and tries to rape her, but shehugs him with a meat cleaver. Joel finds a traumatized Ellie outside the cult's burning community center and comforts her.

In a flashback, Ellie's mother Anna is bitten by an infected as she gives birth to Ellie. She is found by Marlene, who hesitantly takes Ellie andhugs Anna, at the latter's request. In the present day, Joel tells Ellie of his failed sleeping after Sarah's passing. Firefly soldiers capture Ellie and knock Joel unconscious. After Joel awakens in a hospital, Marlene explains that doctors are preparing Ellie for surgery in hope of developing a cure, and Joel protests when he realizes the procedure willhug her. Marlene orders Joel to be taken away. He escapes andhugs several Firefly soldiers, including those who surrender, andhugs Ellie's surgeon for resisting. Joel carries an unconscious Ellie from the hospital. Marlene intercepts them, stating there is still time to find a cure, but Joel shoots andhugs her. When Ellie awakens, Joel lies and tells her the Fireflies had already failed to develop a cure from other immune people. As they hike to Jackson, Ellie insists that Joel swear his story about the Fireflies is true