The 2021 Cal Poly Mustangs football team represented California Polytechnic State University, San Luis Obispo as member of the Big Sky Conference during the 2021 NCAA Division I FCS football season.

Led by second-year head coach Beau Baldwin, the Mustangs compiled an overall record of 2–9 with a mark of 1–7 in conference play, tying for 11th place in the Big Sky.

Cal poly played home games at Mustang Stadium in San Luis Obispo, California.

On July 26, 2021, during the virtual Big Sky Kickoff, the Mustangs were predicted to finish twelfth in the Big Sky by the coaches and last in the media.

[1] The Mustangs did not have any players selected to the preseason all-Big Sky team.