The film was adapted from Jeffery Deaver's 1997 novel of the same name after producer Martin Bregman acquired the film rights; screenwriter Jeremy Iacone condensed the plot down to three murders while staying faithful to the source material, and Christopher Crowe was later brought on for a screenplay polish.

Universal Pictures sold half of the distribution rights to Columbia Pictures because the studio was worried about recouping its investment. Director Phillip Noyce made a personal deal with the studio to cover any budget overruns out of his own pocket in exchange for keeping half of any savings if the film came in under budget.

The role of Lincoln Rhyme was originally written with Al Pacino in mind, since producer Martin Bregman had worked with Pacino on Serpico, Dog Day Afternoon, Scarface, and Carlito's Way, but Pacino was unavailable due to filming The Insider.

Harrison Ford and Sean Connery were suggested by the studio for the lead role before director Phillip Noyce cast Denzel Washington.

For the role of Amelia Donaghy, both Demi Moore and Nicole Kidman were considered before Angelina Jolie was ultimately cast.

To prepare for playing a quadriplegic, Denzel Washington met with several quadriplegics, including actor Christopher Reeve and a police officer who had been paralyzed by a gunshot wound.

Aside from exterior shots filmed on location in Manhattan, New York City, most of the filming took place in Montreal.

A sequel was reported to be in development in June 2023 with Washington and Jolie set to reprise their roles, potentially based on Deaver's 11th novel in the series, The Skin Collector, which is considered a more direct sequel to the original book.

An NBC television adaptation titled Lincoln Rhyme: Hunt for the Bone Collector premiered in January 2020 but was canceled after one season. Director Phillip Noyce briefly consulted on the project but declined to direct the pilot, later criticizing the show's casting choices and its attempt to lighten the tone of the material.