Set in March 1986, eight months after the events of the third season, the fourth season is split between different plotlines.

The first plotline takes place in Hawkins, where several teenagers are killed in mysterious ways. It features Dustin Henderson, Max Mayfield, Lucas and Erica Sinclair, Steve Harrington, Nancy Wheeler, Robin Buckley, and Eddie Munson, the leader of the Hellfire Club; a Dungeons & Dragons group that includes Dustin and his friends. Eddie becomes the prime murder suspect and is hunted down by Jason Carver and members of the basketball team, who believe that Eddie killed Jason's girlfriend Chrissy Cunningham using satanic powers. Dustin and friends investigate and discover that the murders were carried out by a powerful being that lives in the Upside Down, an entity they later dubbed Vecna.

The second plotline involves Mike Wheeler visiting Eleven, Will, and Jonathan Byers at their new home in California. Due to the events in Hawkins and the imminent danger to her friends, Eleven goes with Dr. Martin Brenner and Sam Owens to a secret facility to help her regain her powers. Mike, Will, Jonathan, and Jonathan's friend Argyle try to track Eleven down.

The third plotline follows Joyce Byers and Murray Bauman, who learn that Jim Hopper may still be alive and are told to bring money to arrange his transfer. Meanwhile, in a Russian gulag in Kamchatka, Hopper is held prisoner and is forced, alongside other inmates, to battle a Demogorgon that the Russians have captured.