The first plotline takes place in Hawkins, where a series of mysterious teenage murders begin haunting the town. Eddie Munson, leader of the Hellfire Club, Hawkins High School Dungeons & Dragons group, becomes a prime suspect in the murders after senior cheerleading captain Chrissy Cunningham dies in his trailer. Bianca Harrington, Dustin Henderson, Lucas and Erica Sinclair, Max Mayfield, Steve Harrington, Nancy Wheeler, and Robin Buckley begin investigating to clear Eddie's name. They discover that the true perpetrator is a powerful being who resides in the Upside Down, whom they later dub "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. Sam Owens to a secret facility in Nevada to regain her powers, where she is reunited with Dr. Martin Brenner and forced to confront her past in Hawkins National Laboratory with the aid of an isolation tank. With the military searching for Eleven, Mike, Will, Jonathan, and new friend Argyle try to track her down first.
The third plotline follows Joyce Byers and Murray Bauman as they venture to Russia upon learning that Jim Hopper may still be alive. Meanwhile, Hopper is held in a Soviet prison camp in Kamchatka, where he and the other inmates are forced to battle a Demogorgon that the Russians have captured.