The top-ranked Williams twice lost five games in a row Monday but finished with a flourish and beat No. 17-seeded Zheng Jie 7-5, 5-7, 6-3.
Also advancing was No. 5-seeded Venus Williams, who beat Agnieszka Radwanska 4-6, 6-1, 6-4. The Williams sisters could renew their sibling rivalry in the semifinals Thursday.
Serena Williams is seeking a record sixth Key Biscayne title and her third in a row. Her reign was in danger when she fell behind 0-2, 15-40 serving in the third set, but she rallied to take the lead, then swept the final eight points.
Williams won despite being broken six times and committing 43 unforced errors.