2021 MUSC Health Women's Open – Singles

Astra Sharma won her first WTA Tour singles title, defeating Ons Jabeur in the final of the second 2021 Charleston Open, 2–6, 7–5, 6–1.

The second tournament was the 50th edition of the Charleston Open that featured featuring consecutive events, with the 2021 Volvo Car Open being the first. The second Charleston tournament was organised with a single-year license in 2021.

Seeds
• # 🇹🇳 Ons Jabeur (final)

• # 🇵🇱 Magda Linette (first round)

• # 🇺🇸 Shelby Rogers (quarterfinals)

• # 🇫🇷 Alizé Cornet (first round, retired)

• # 🇯🇵 Misaki Doi (first round, retired)

• # 🇦🇺 Ajla Tomljanović (second round)

• # 🇺🇸 Lauren Davis (second round)

• # 🇺🇸 Madison Brengle (second round)

Seeds
• # 🇲🇽 Renata Zarazúa (moved to main draw)

• # 🇷🇺 Natalia Vikhlyantseva (moved to main draw)

• # 🇺🇸 Francesca Di Lorenzo (moved to main draw)

• # Leonie Küng (first round)

• # 🇺🇸 Caroline Dolehide (first round)

• # 🇺🇸 Usue Maitane Arconada (first round)

• # 🇯🇵 Kurumi Nara (qualifying competition)

• # 🇦🇺 Arina Rodionova (withdrew)

Qualifiers
• # 🇺🇸 Claire Liu

• # 🇦🇺 Storm Sanders

• # 🇺🇸 Alycia Parks

• # 🇺🇸 Grace Min