The 2021 South Point 400 was a NASCAR Cup Series race held on September 26, 2021, at Las Vegas Motor Speedway in Las Vegas. Contested over 267 laps on the 1.5 mi (2.4 km) asphalt intermediate speedway, it was the 30th race of the 2021 NASCAR Cup Series season, the fourth race of the Playoffs, and the first race of the Round of 12.

The 2021 NASCAR Cup Series was the 73rd season for NASCAR professional stock car racing in the United States and the 50th season for the modern era Cup Series. The season started at Daytona International Speedway with the Busch Clash, where it was the first year that the non-points event was run on the track's road course layout instead of the oval. That race was followed by the Bluegreen Vacations Duel qualifying races, and the 63rd running of the Daytona 500, the first points race of the season. The regular season also ended at Daytona with the 2021 Coke Zero Sugar 400 on August 28, where Kyle Larson won the Regular Season Championship. Following the 2021 Xfinity 500 at Martinsville Speedway on October 31, Chevrolet claimed its 40th Manufacturer's Championship and its first since 2015. The NASCAR playoffs ended with the NASCAR Cup Series Championship Race at Phoenix Raceway on November 7 with Larson earning his first Cup Series championship after a 10-win season.