Five years after the events of the first game, Joel and Ellie are living in Tommy's settlement in Jackson, Wyoming. During this time, Ellie has made friends with Dina and Jesse, and entered a relationship with Dina after the couple broke up. In the winter, when Joel and Tommy go missing while observing the movement of nearby Infected, Ellie and Dina go to investigate.

Joel and Tommy encounter Abby, and the group escape a large horde. Abby reveals herself as the leader of a small group within the larger Washington Liberation Front and the daughter of one of the Firefly surgeons Joel killed while saving Ellie, and beats Joel to death as Ellie finds him. Though affected by the incident, Ellie swears revenge. In the spring, Tommy, frustrated that Jackson does not have the resources to fight the WLF, pursues them to their base in Seattle on his own.

With authorization from Tommy's wife Maria, Ellie and Dina go after Tommy, who has already killed several WLF members. While avoiding WLF patrols in Seattle, the pair are attacked by a large group of Infected and, upon escaping, Ellie reveals her immunity to Dina, who in turn reveals she is pregnant. The next day, with Dina physically weakened by her pregnancy, Ellie pursues Tommy alone and encounters Jesse, who had followed them to Seattle, but has been wounded, leaving Ellie to continue her journey alone. While seraching for a member of Abby's group named Nora, she encounters the Seraphites, a group of religious fanatics who are battling the WLF over control of Seattle.

Eventually, Ellie tracks down Nora and beats her for information on Abby's location. As Nora succumbs to her injuries, Ellie learns she is a former Firefly, causing her to recall how, two years ago, she investigated the hospital Joel rescued her from and learned he lied about the Fireflies being unable to find a cure. The following day, Ellie heads out to track down Abby while Jesse goes after Tommy, upon learning the WLF potentially found his location. Ellie comes across two more members of Abby's group, Owen and Mel, whom she is forced to kill, only to then discover Mel was pregnant, much to her horror.

After Ellie rendezvouses with Dina, Jesse, and Tommy, the group decide to return to Jackson, but are ambushed by Abby, who kills Jesse and holds Tommy hostage, while explaining her motivation to kill Joel. She then narrates her actions in the past three days, prompting a flashback. Upon learning that Owen had gone missing while investigating Seraphite activity, Abby confronted the WLF leader, Isaac (Jeffrey Wright), for keeping the issue a secret, who revealed some intelligence he had indicating Owen might have joined the Seraphites, and explained his plan to assault the Seraphites' island settlement in order wipe them out completely.

Abby then went searching for Owen and, upon being captured, was rescued by Yara and her brother Lev, both rogue Seraphites. She eventually found Owen who, disillusioned with the pointless war betweeen the WLF and Seraphites, was attempting to sail to Santa Barbara, where the Fireflies were supposedly regrouping. Afterwards, with Yara's arm broken, Abby took her to Owen and Mel for medical attention, and retrieved medical supplies from the WLF hospital alongside Lev, where they encountered Nora, who helped them, and Lev revealed he was on the run from the Seraphites for shaving his head, against the cult's rules.

After Yara's arm was amputated, Lev ran away to see his mother, forcing Abby and Yara to pursue him. Along the way, they encountered Abby's friend Manny, who later was killed by Tommy. The pair eventually found Lev, who was forced to kill his mother when she attacked him, only to be forced to flee when the WLF assault on the Seraphites begun.

Yara sacrificed herself to allow Abby and Lev to escape, killing Isaac in the process. The pair then returned to find Owen and Mel dead, and a map left behind by Ellie leading to her hideout.