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Cal Poly began playing women's basketball at the intercollegiate level in 1974 in the AIAW, with NCAA-sponsored play beginning in 1981.

The Mustangs have had three teams tie for the school record for wins (21) in a season: the 1981–82 squad coached by Marilyn McNeil and the 2008–09 and 2012–13 squads coached by Faith Mimnaugh.

Following Sharon Chatman (1974–75) and Mary Stallard (1975–79), McNeil coached Cal Poly from 1979 to 1986 before becoming an athletics administrator on campus. In 1994, McNeil departed Cal Poly to become the athletic director at Monmouth University, from which she retired in 2021. Taking over after Jill Orrock (1986–95) and Karen Booker (1995–97), Mimnaugh served as head coach from 1997 to 2022. Shanele Stires, former WNBA player and head coach at Cal State East Bay, was hired as the team's seventh head coach on April 14, 2022.

The furthest the team has advanced came in March 2013, when Cal Poly defeated Pacific 63–49 to win the Big West Conference women's basketball tournament, their first conference tournament championship after two previous years of regular-season titles. Seeded 14th in their ensuing NCAA Tournament appearance, they lost 85-55 to Penn State in the first round. Cal Poly qualified for the semifinal round of the Big West Tournament in March 2020, but the postseason was abruptly canceled due to COVID-19 after the Mustangs had won comfortably twice in the tournament's earlier rounds.

The team has made four WNIT appearances, losing to California (Berkeley) in 2011, Washington in 2012, San Diego in 2014, and Pacific in 2024.