Producer Charles Marquis Warren based Rawhide on three sources: his own 1958 film Cattle Empire, Borden Chase's novel Chisholm Trail (which also inspired Red River), and the real diary of trail boss George C. Duffield written during an 1866 cattle drive from San Antonio to Sedalia.

The opening monologues delivered by Gil Favor in each episode were styled to resemble the entries in George C. Duffield's actual trail diary, giving the show an extra measure of authenticity.

Several actors from Charles Marquis Warren's 1958 film Cattle Empire, including Paul Brinegar, Steve Raines, Rocky Shahan, and Charles H. Gray, went on to appear in Rawhide.

Filming for the first season took place at Universal-International Studios in Hollywood, while the extensive railroad scenes of the third season were shot in just one month on the Sierra Railroad in Tuolumne County, California.

The show had a grueling production schedule, filming weekly with only a three- to four-month break between seasons; lead actors could usually only get time off if their character was written as away on business, or when an episode focused on a smaller group of the cast.

The theme song 'Rawhide' was written by Ned Washington and composed by Dimitri Tiomkin in 1958, sung by Frankie Laine, with the orchestra and chorus conducted by a young John Williams, credited at the time as 'Johnny Williams'.

The 'Rawhide' theme became widely popular and was later featured in films such as The Blues Brothers and Shrek 2.

DVD releases of the series heavily promote Clint Eastwood as the lead star due to his later fame, even though the original show credits for seasons one through seven actually list the late Eric Fleming (as Gil Favor) as the top-billed cast member, with Eastwood as co-star.

The eighth and final season's animated title sequence was created by Ken Mundie of DePatie-Freleng Enterprises.