2021 US Open – Mixed doubles

Desirae Krawczyk and Joe Salisbury defeated Giuliana Olmos and Marcelo Arévalo in the final, 7–5, 6–2 to win the mixed doubles tennis title at the 2021 US Open. By winning the title, Krawczyk and Salisbury received their third and second major mixed doubles title, respectively. Their victory together made Krawczyk the first player to win three consecutive mixed doubles major trophies since Mahesh Bhupathi in 2005 and 2006, and the seventh player in the Open Era to win three mixed doubles titles in a single season. Salisbury became the first man to win both the men's doubles and mixed doubles titles at the US Open in the same year since Bob Bryan in 2010.

Arévalo became the first player from Central America to reach a Grand Slam final.

Bethanie Mattek-Sands and Jamie Murray were the two-time defending champions, having won the most recent editions in 2018 and 2019, but lost in the first round to Andreja Klepač and Joran Vliegen.