The 2021 championship game was the seventh to feature two teams from the same conference. Stanford and Arizona met twice during the regular season, with Stanford winning both meetings. The Cardinal recorded an 81–74 win on the road on January 1, 2021, and defeated the Wildcats again at home, 62–48, on February 22, 2021. This was the 86th meeting all-time between the teams, with Stanford leading the series 71–14. Regardless of the game’s result, the winner would have been the first national champion from the Pac-12 Conference since Stanford in 1992.

Stanford, led by 35th-year head coach Tara VanDerveer, finished the regular season with a record of 22–2, including wins over five ranked teams. The Cardinal recorded a 19–2 conference record, earning them the No. 1 seed in the Pac-12 Tournament, where they defeated No. 8 seed USC, No. 5 seed Oregon State, and No. 3 seed UCLA en route to their 14th Pac-12 tournament championship. By virtue of winning their conference tournament, they were awarded an automatic bid to the NCAA Tournament, where they received a No. 1 seed and were placed into the Alamo Regional. In the tournament, they defeated No. 16 seed Utah Valley and No. 8 seed Oklahoma State to reach the Sweet Sixteen for the 27th time in program history. The Cardinal then defeated No. 5 seed Missouri State and No. 2 seed Louisville to win the Alamo Regional and reach their 14th Final Four.

In the Final Four, Stanford defeated fellow No. 1 seed South Carolina by one point to reach their fifth title game; they entered seeking their third national championship.