The American, chasing her 12th grand-slam title, eased through in 87 minutes and will next play 22nd seed Daniela Hantuchova of Slovakia.
When Williams beat Martinez Sanchez at the French Open in May, she labelled her a "cheat" over an incident when the Spaniard claimed she had hit a winner only for television replays to show the ball had bounced off her arm.
The world number 43 gave Williams a brief scare when she grabbed a 3-1 lead in the second set but the American second seed broke back and then repeated the feat in a prolonged 11th game before serving out to love for victory.
Del Potro Muscles Past Melzer to Reach Round Three
Argentine sixth seed Juan Martin Del Potro flexed his rippling muscles as he overpowered Austrian Juergen Melzer 7-6 6-3 6-3 to reach the third round of the U.S. Open on Friday.
Wearing a sleeveless black shirt, Del Potro showed off his biceps on a gloriously sunny day in New York as he gave Melzer the run around on a sparsely filled Louis Armstrong Stadium.
The Argentine fought back from a break down in the opening set to take the tiebreak 8-6 and from then on had little trouble overcoming the man who had ended former champion Marat Safin's grand slam career in the previous round.
Del Potro, who reached the last eight here 12 months ago, fired an ace to extend his record against Melzer to 5-0 and will next take on Uruguay's Pablo Cuevas or another Austrian, Daniel Koellerer.
