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San Francisco began play in 1976. Their first postseason appearance was in the 1980 AIAW National Division I Basketball Championship, losing 92–58 to BYU in the First Round. They made appearances in the NCAA Tournament in 1995, 1996, 1997, 2016, with a Sweet Sixteen appearance in 1996. That year, USF (ranked as a 5 seed) beat Florida 68–61, and Duke 64–60 before losing to Connecticut 72–44. They have made the WNIT three times. They played in the NCAC from 1977 to 1982 and the NORPAC from 1982 to 1985 before joining the West Coast Conference in 1985. As of the end of the 2015–16 season, the Dons have an all-time record of 546–595.

The Dons saw a major restructuring in the offseason between the 2022–23 and 2023–24 seasons. Two of their graduate-level starters, Ioanna Krimili (presently the 3-point record holder at USF) and Kennedy Dickie, transferred to UC Berkeley and Portland respectively. The San Francisco Chronicle described the transfers as happening all across the West Coast Conference, both between schools and out of the conference.

Molly Goodenbour abuse allegations

In 2022, a lawsuit was filed against head coach Molly Goodenbour with USF named as a secondary defendant by former players Marta and Marija Galic. The Galic sisters, both overseas student athletes from Croatia, allege that Goodenbour “archaic and abusive conduct”, highlighting an instance where Goodenbour refused to allow Marta Galic to go to the bathroom and thereby forcing her to urinate on herself in front of her teammates. Marija Galic additionally states in the filing that Goodenbour succumbed her to verbal and psychological abuse, causing her to suffer from nervous breakdowns, and that Goodenbour did not follow the proper concussion protocols.

Goodenbour and USF responded to the suit by denying an intent to cause the harm the sisters described. Both further argued that the bathroom incident described by the sisters never happened. Mike Vartain, a lawyer for USF, commented Goodenbour would never want a player to urinate their pants, and that no such prohibition on going to the bathroom without asking would exist.

The scandals revolving around Goodenbour, concurrent with abuse scandals surrounding Dons baseball coach Nino Giarratano, are credited with inciting the 2022 resignation of USF's athletic director Joan McDermott.