Three years after millions of people – some 2% of the world’s population – vanished into thin air, residents of Mapleton, NY weigh the pros and cons of a “Heroes Day” tribute to the local “Departed.” Attempting to maintain a sense of normalcy in his strained community, police chief Kevin Garvey faces additional challenges at home with his daughter, Jill, who’s lost in a cloud of apathy with her friend Aimee, and son, Tom, who has gravitated to a cult led by the charismatic Holy Wayne. Also of concern is a silent, white-clad group of chain-smoking men and women called the Guilty Remnant, who team up in pairs to stake out people and places around town. As tension in Mapleton escalates, the lives of Laurie, an unexpected member of the Guilty Remnant, and Meg, a recently engaged young woman, converge.

In the wake of a series of disturbing encounters, Kevin pays a visit to a therapist. Tom finds himself in a precarious situation with Christine, a favorite of Wayne’s. A frustrated Meg is asked to part with pieces of her past. Jill and Aimee tail Nora Durst, who became a local celebrity when her entire family disappeared in the Departure.

Nora goes to New York for the second annual Departure Related Occupations and Practices (DROP) conference, but discovers that someone else has her ID badge, so she searches the convention as a "Guest," and has encounters with a salesman, an author and a rogue attendee.

After learning his father has escaped the psychiatric hospital, Kevin orders an APB to track him down. Jill attempts to break an endurance record. Holed up in Indiana, a disillusioned Tom makes an unsettling discovery.

An unexpected ally helps Kevin get out of a jam near the town of Cairo. Meanwhile, an elaborate Memorial Day initiative by the Guilty Remnant plunges the town of Mapleton into chaos. Holy Wayne grants a final wish, Tom copes with his new reality. Nora makes a life-changing decision.