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Winthrop began play in 1969. From 1982 to 1986, they played in the NAIA before joining the NCAA in 1986. They made an appearance in the WNIT in 2013, their first postseason appearance in school history. They beat Florida Gulf Coast 65–51 to win their first ever postseason game before they lost to the University of Florida 85–53 in the Second Round. In 2014, they won the Big South Conference tournament and won the bid to go to the NCAA Tournament, both firsts for the program. They lost 87–45 to Duke University in the First Round.

Lynette Woodard Era (2017–2020)

On March 28, 2017, Lynette Woodard was named head coach of Winthrop. The season before Woodard took over as head coach, WU was 1–17 (.056) in conference play and 2–29 (.065) overall. They also suffered the worst loss in the history of women's NCAA basketball to Baylor, losing by 108 points . During her tenure, WU improved its record to 8–28 (.285) in conference play and 13–47 (.276) overall.

Woodard was fired on March 24, 2020.

Semeka Randall Era (2021–present)

Former WNBA player and University of Tennessee alum, Semeka Randall was named head coach in April 2021.