The 2021 USC Upstate Spartans baseball team represented the University of South Carolina Upstate during the 2021 NCAA Division I baseball season. The Spartans played their home games at Cleveland S. Harley Baseball Park as a member of the Big South Conference. They were led by head coach Mike McGuire, in his second season at Upstate. USC Upstate finished the season with a 37–16 with a 28–12 Big South record. They were eliminated in the losers bracket first round of the Big South Tournament.