Ellie (Ashley Johnson) is a fourteen-year-old orphan and the other main playable character in the game, and one of the few characters to have never known life before the infection. Much of her backstory is revealed in the additional content The Last of Us: Left Behind and the comic book miniseries The Last of Us: American Dreams.

After surviving a bite from the Infected, Ellie is tasked to Joel to be escorted to the Fireflies. Initially annoyed by Joel's surliness, Ellie starts to feel a strong attachment to him. After experiencing a traumatizing encounter in the Winter, in which Ellie is nearly raped and murdered by a band of cannibals, she becomes withdrawn and introverted. When Joel finally gets her to the Fireflies, it is discovered she has a mutant strain of the Cordyceps fungus growing on her brain, which may be used to create a vaccine; in order to extract the fungi, an operation on Ellie's brain is required that will likely kill her. While she is being prepared for surgery, Joel makes his way to the operating room and carries her to safety. When Ellie awakens from unconsciousness, Joel lies by telling her the Fireflies found many other subjects, and had stopped looking for a cure. Ellie later confronts him about it, demanding to know the truth. When he reassures her he is telling the truth, she replies with "Okay".