The U.S. Tennis Association did not give reasons for the three withdrawals Monday.
Kuznetsova won the 2004 title at Flushing Meadows, and added the 2009 French Open championship. She's been ranked as high as No. 2 but is only 48th this week.
The 15th-ranked Kanepi withdrew from Wimbledon and the London Olympics because of a heel injury.
Pennetta is ranked 18th.
The U.S. Open draw is Thursday. Play begins next Monday.