The original 1980 television pilot, titled Pirate's Key, was set in Florida; when CBS picked up the show, the brothers' home was changed to San Diego, California.

Creator Philip DeGuere said the show was inspired by a CBS executive's request for a modern 'Butch and Sundance' as well as a spec pilot he had read about a divorced husband-and-wife detective team, written by Bob Shayne, whom DeGuere then hired to write for the first two seasons.

Although the show remained set in San Diego throughout its run, filming actually moved to Los Angeles after the first season due to production costs and low ratings.

Despite Rick being portrayed as a few years older than A.J. in the show, actors Gerald McRaney and Jameson Parker were both born in 1947, only three months apart in age.

Simon & Simon was nearly cancelled in 1982 due to low ratings, but CBS moved it to Thursdays at 9 p.m. following the popular Magnum, P.I., which helped boost its audience significantly.

A two-hour crossover story began on the popular Magnum, P.I. episode 'Ki'is Don't Lie' and concluded on the Simon & Simon episode 'Emeralds Are Not a Girl's Best Friend', designed to carry Magnum's audience over to the lesser-known show.

A second, alternate ending for the crossover was filmed so that the Magnum, P.I. episode could be rerun as a stand-alone story; as a result, the original crossover versions of both episodes were kept out of reruns for many years before eventually appearing on DVD.

A.J. Simon appeared on the Whiz Kids episode 'Deadly Access', and in return several Whiz Kids characters appeared the following night on the Simon & Simon episode 'Fly the Alibi Skies'.

The show's second and more recognizable theme song, featuring an electric bottle-slide guitar and saxophone, was composed by Barry De Vorzon (who had earlier written the theme for S.W.A.T.) together with Michael Towers, replacing the first season's theme 'Best of Friends' by the Thrasher Brothers.

In 2012, Adult Swim's special The Greatest Event in Television History featured a shot-for-shot remake of the Simon & Simon opening sequence starring Adam Scott and Jon Hamm as A.J. and Rick, hosted by Jeff Probst.