The destruction of an asteroid headed for Earth releases chemical fallout, causing cold-blooded animals to mutate into large monsters and kill off most of humanity. During the evacuation of Fairfield, Joel Dawson is separated from his girlfriend Aimee but promises to find her, shortly before his parents are killed.
Seven years later, Joel lives in one of many bunkers underground called “colonies”, where all survivors but he have romantically paired up with each other while fighting monsters and seeking supplies. Joel instead is left behind in the kitchen, as he freezes in dangerous situations. When a giant ant breaches his colony, killing Connor, Joel sets off on a quest to reunite with Aimee so he doesn’t end up alone.
Passing through the suburbs, Joel is attacked by a giant toad-monster but is saved by a stray dog named “Boy”, who follows Joel on his journey, warning him against poisonous berries and other dangers. Joel falls into a nest of worm-monsters called “Sand-Gobblers”, when two survivors, Clyde Dutton and Minnow, rescue him. They are heading north to the mountains, where fewer monsters live due to the colder weather and higher elevation. They teach Joel some basic survival skills, and that not all monsters are hostile, demonstrating how “You can always tell in their eyes”. They invite Joel to stay with them, but he insists he must find Aimee. As they part ways, Clyde gives Joel a grenade.
Continuing west, Boy becomes trapped by a giant centipede-monster. Joel freezes, but eventually saves Boy with his crossbow. Sheltering in an abandoned motel, they meet a robot named Mav1s. Before her battery dies, Mav1s powers his radio long enough to briefly contact Aimee. Other survivors have reached her colony, promising to lead them to safety. The next day Joel and Boy are attacked by a Queen Sand-Gobbler. They hide, but Boy barks, giving away their position. Joel kills the Queen with the grenade. He yells at Boy for putting them in danger, causing Boy to run away. After swimming across a pond, Joel is covered in poisonous leeches and hallucinates, but is rescued before he collapses.
Joel wakes to finally see Aimee. She leads a beach colony of elderly survivors who depend on her. He is introduced to the survivors, Cap, and his crew. As everyone celebrates their imminent departure, Aimee confesses she is glad to see Joel, but has become a different person and is still mourning someone. Joel decides to return to his colony, contacting them on the radio and learning that it has become unsafe and that they too must leave. Cap sends Joel some berries, which he recognizes as poisonous. Realizing Cap is not to be trusted, he rushes to warn Aimee but is knocked unconscious.
Joel, Aimee, and the rest of her colony awaken tied-up on the beach. Cap reveals that his group is there to steal supplies and that their yacht is towed by a crab-monster controlled with an electrified chain. Cap sets the crab to feed on the colonists, but Joel and Aimee escape and are able to fight for their lives, and Boy returns to help. Joel has the opportunity to kill the crab, but he realizes it is not hostile by looking into its eyes, and shoots the electrified chain, freeing it. The crab leaves Joel unharmed and instead kills Cap and his crew, sinking the yacht in the process.
Joel recommends Aimee and her colony head north. They share a romantic goodbye kiss, and Aimee promises she will find him. Joel treks all the way back to his colony, and they too decide to head to the mountains. On the radio, Joel inspires other colonies to take to the surface. As everyone heads north, Clyde and Minnow, already in the mountains, wonder if Joel will survive the next journey.