After the destruction of an asteroid headed for Earth, the chemical fallout causes all cold-blooded animals to mutate into large monsters. During the evacuation of Fairfield, Joel Dawson is separated from his girlfriend Aimee but promises to find her, and his parents are killed.
Seven years later, Joel lives in one of many underground bunkers called “colonies”, where other survivors, except for him, have romantically paired up with each other while fighting monsters and scavenging for supplies. Joel instead is left behind in the kitchen, as he is notorious for freezing in dangerous situations. When a giant ant breaches his colony, killing one of the survivors, Joel sets off on a quest to reunite with Aimee so that 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 the colder weather and higher elevation means fewer monsters. They teach Joel some basic survival skills, and how not all monsters are hostile, demonstrating how “You can always tell in their eyes”. They invite Joel to stay with them, but Joel insists that he must find Aimee. As they part ways, Clyde gifts Joel with a grenade.
As Joel continues west, Boy becomes trapped by a giant centipede-monster. Joel freezes, but eventually shoots and kills the monster with his crossbow, saving Boy. 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, where he learns that new survivors have reached her colony, promising to lead them away 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 but yells at Boy for putting them in danger, causing Boy to run away. After swimming across a river, 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. Joel is introduced to the new 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 she had become close to. Joel decides to return to his colony and contacts them on the radio, learning that it has become unsafe and that they too must leave soon. 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 that Cap controls 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 determines that the crab 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, and sinks the yacht.
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.