The 2021 Winston-Salem Open was a men's tennis tournament played on outdoor hard courts.

It was the 52nd edition of the Winston-Salem Open (as successor to previous tournaments in New Haven and Long Island), and part of the ATP Tour 250 Series of the 2021 ATP Tour.

It took place at Wake Forest University in Winston-Salem, North Carolina, United States, from August 21 through August 28, 2021.

It was the last event on the 2021 US Open Series before the 2021 US Open.

[1] *per team 1 Rankings are as of August 16, 2021 [2] The following players received wildcards into the singles main draw: The following player received entry using a protected ranking into the singles main draw: The following players received entry from the qualifying draw: The following players received entry as lucky losers: 1 Rankings are as of August 16, 2021 The following pairs received wildcards into the doubles main draw: