CBS originally ordered a 15-minute pilot presentation of the project in March 2008 before deciding to move forward with the series.

The show was intended to be an anthology series, with each new season set to feature a new setting and new characters, but CBS cancelled it after just one season on July 14, 2009.

During a major retooling in May 2008, six of the original fifteen pilot-presentation cast members were replaced, including Ryan Merriman, Samantha Noble, Bill Dow, and Bill Pullman, who had played Henry Dunn, Trish Wellington, Sheriff Mills, and Uncle Marty respectively.

Only two actors were told the length of their contracts in advance: Richard Burgi, because his character's death was designed as a major turning point in the series, and Harry Hamlin, since his contract covered only a single episode.

The actors were not informed about their characters' deaths until the day the relevant script was handed to them, keeping the killer's identity and death order secret even from the cast.

The series was filmed on Bowen Island, a small island municipality about two kilometers west of Vancouver, British Columbia, as well as at the University of British Columbia.

A companion social web series called Harper's Globe, created by EQAL (the studio behind lonelygirl15), ran for sixteen weekly episodes starting March 18, 2009, and starred Melanie Merkosky as journalist Robin Matthews.

The character Ben, the first victim to die in Harper's Island, actually made his first appearance in an episode of the companion web series Harper's Globe.

Harper's Island averaged 9.36 million viewers and ranked #50 in Nielsen ratings by the end of its run, and gained a strong cult following over time, with some critics and fans considering it ahead of its time.