The series began as a spin-off of Jake and the Fatman, where Dr. Mark Sloan first appeared in the season four episode 'It Never Entered My Mind' as a widower with no sons, quite different from the family-oriented character he later became.

Dick Van Dyke was considered for the lead role of Dr. Mark Sloan after receiving positive reviews for his dramatic, villainous role in the 1990 movie Dick Tracy, a stark contrast to the warm doctor character he would go on to play.

The role of Steve Sloan, Mark's police detective son, was played by Barry Van Dyke, Dick Van Dyke's real-life son, and over the show's run at least eight members of the Van Dyke family appeared in various roles, including Dick's brother Jerry, his daughter Stacy, and Barry's four children.

In the pilot, Dr. Mark Sloan had hobbies of tap dancing and clarinet playing, but these traits were considered distracting and were gradually toned down and removed as the series developed.

The first season began filming in July 1993 in Denver, Colorado, partly because the same Viacom production team (led by Hargrove and Silverman) was already filming the Perry Mason TV movies there with Raymond Burr, allowing the two productions to share resources at the same hotel and locations.

Production shifted from Denver to Los Angeles without any explanation after only the first eight episodes, following the death of Raymond Burr and the wrap of the final Perry Mason production filmed there in late 1993.

Mark Sloan's Malibu beach house, used as a filming location starting in the third season, is a real house on Broad Beach Road in Malibu that was later also used as a filming location for the Disney Channel show Hannah Montana.

The show frequently featured veteran actors reprising or echoing their classic TV roles, such as Mike Connors returning as Mannix, Andy Griffith reprising Ben Matlock, Barbara Bain reprising Cinnamon Carter from Mission: Impossible, and Jack Klugman playing a character modeled on his Quincy, M.E. role.

In the episode 'Obsession, Part 2,' archival black-and-white footage of Dick Van Dyke as Rob Petrie from The Dick Van Dyke Show was inserted via CGI so that Dr. Sloan appears to walk past him in a radio station, with Sloan then breaking the fourth wall to look at the audience.

Executive producer Fred Silverman required that at least one episode per season serve as a backdoor pilot to test potential spin-off characters, resulting in numerous unsold pilots such as 'Sister Michael Wants You' with Delta Burke, 'Hard-Boiled Murder' as a potential Mannix revival, and a proposed Charlie's Angels-style series called G-Girls that Dick Van Dyke refused to participate in, ensuring it was never filmed.

The season 5 backdoor pilot 'Hard-Boiled Murder,' reuniting Mike Connors as Mannix, achieved strong ratings and prompted real discussions about a new Mannix series, but concerns over Connors' age and the show's older demographic led CBS and UPN to pass on it.