Eddie Brock and the Venom symbiote are hiding in a bar in Mexico after their fight with Carnage, with Eddie named the prime suspect in the murder of Patrick Mulligan. To clear his name, Eddie heads to New York City. Unbeknownst to them, a creature called a Xenophage is tracking Eddie, while Rex Strickland, overseeing a government operation at Area 51, learns about the situation. Mulligan, who survived his encounter with Carnage, is captured and bonded with a symbiote.

While trying to escape to New York, Eddie and Venom are ambushed by the Xenophage and crash into a desert. Venom explains that the Xenophages were sent by Knull, the creator of the symbiotes, to retrieve a Codex formed when a symbiote resurrects its host. After a chaotic encounter with Strickland's team, Eddie meets a family heading to Area 51 and gets a ride with them.

In Las Vegas, they are again attacked by the Xenophage, and Strickland’s team captures them. Venom is freed and reunites with Eddie just as Strickland shoots him, attracting the Xenophage. In a final act of sacrifice, Venom merges with the Xenophages to destroy the Codex. Eddie later wakes in a hospital to learn he has a pardon but must keep the events secret. As he reflects on Venom at the Statue of Liberty, Knull vows to reclaim the universe, while a cockroach crawls out from the ruins of Area 51, hinting at Venom’s return.