The series is based on the non-fiction book 'Dopesick: Dealers, Doctors, and the Drug Company that Addicted America' by Beth Macy, who also served as an executive producer on the show.

Hulu ordered the limited series in June 2020, with production initially announced to involve Fox 21 Television Studios before it was replaced by 20th Television.

Barry Levinson directed the entire limited series and also served as an executive producer, alongside creator Danny Strong and star Michael Keaton.

Most characters in the series are composites representing the broad effects of the opioid epidemic, with exceptions being the Sackler family, several government figures, and prosecutors Rick Mountcastle and Randy Ramseyer, who are based on real people.

Principal photography took place from December 2020 to May 2021 in Richmond and Clifton Forge, Virginia; North Carolina and Georgia were also considered but Virginia was chosen for its tax incentives and locations.

The first episode screened at the Virginia Film Festival on October 30, 2021, followed by a discussion with creator Danny Strong and author Beth Macy.

Michael Keaton's performance as Dr. Fennix earned him the Emmy, Golden Globe, Screen Actors Guild Award, and Critics' Choice Television Award for Lead Actor.