The second 2021 Charleston Open (branded as the MUSC Health Women's Open for commercial reasons) was a tournament on the 2021 WTA Tour. It was played on outdoor green clay courts in Daniel Island. It was held one day after the 48th edition ended and was a replacement tournament for other tournaments that were not held because of travel restrictions, and organised by Charleston Tennis with a single-year licence in 2021, held at Family Circle Tennis Center from April 12 to 18, 2021.
The following players received wildcards into the main draw:
The following player received entry as a special exempt:
The following players received entry from the qualifying draw:
The following pair received a wildcard into the doubles main draw:
The following pair received entry into the doubles main draw using a protected ranking:
The following pair received entry into the doubles main draw as an alternate: