The series is based on the Rizzoli & Isles novels by Tess Gerritsen, with the pilot episode largely adapted from the second novel, The Apprentice, while Jane Rizzoli was first introduced in the first novel, The Surgeon.

The show was originally developed under the working title 'Rizzoli' on TNT's development slate as early as March 2008, and only became 'Rizzoli & Isles' when TNT greenlit the pilot to series in late January 2010.

Angie Harmon was the first actress cast in the title role of Jane Rizzoli, and Sasha Alexander won the role of Maura Isles after auditioning together with Harmon.

The series was filmed primarily in Hollywood, Los Angeles, at Paramount Pictures studios rather than on location in Boston.

Production on the fourth season was suspended in August 2013 after cast member Lee Thompson Young, who played Barry Frost, was found dead at his Los Angeles apartment from a self-inflicted gunshot wound; his character was subsequently killed off in a car accident in the season five premiere.

After Lee Thompson Young's death, a new character, crime scene analyst Nina Holiday played by Idara Victor, was introduced in the second half of season five, though producers stated she was not meant to replace Frost but rather to give existing characters new dynamics.

The series premiere drew 7.55 million viewers, setting a record as the highest-rated debut for a commercial-supported cable series and becoming the second-highest debut ever for a basic cable TV series, behind only Raising the Bar's 2008 commercial-free premiere.

The show has been widely discussed for its perceived lesbian subtext between Rizzoli and Isles, with outlets like The Advocate linking this to its popularity; Harmon said the characters are 'straight' and 'just best friends,' while Alexander said she wasn't initially aware of the subtext but felt it reflected the characters' chemistry.

Due to a sponsorship deal between MillerCoors and Turner Broadcasting for the summer 2010 season, the first season featured product placement for MGD 64, including billboards visible in the backgrounds of some scenes.