Neither Williams nor Djokovic has played a match since early exits at the Rio Olympics. Williams later said she was dealing with a right shoulder problem, while Djokovic said his left wrist was sore.
Williams could have been overtaken atop the WTA rankings by No. 2 Angelique Kerber but stayed at No. 1 this week. The U.S. Tennis Association adhered to the men's and women's rankings in announcing the seedings Tuesday.
This is the fifth time Williams is the top seed at Flushing Meadows; she has won the tournament six times. Last year, she was stunned in the semifinals by Roberta Vinci, stopping the American's bid for a calendar-year Grand Slam.
The draw for the year's last major tennis tournament is Friday. Play begins Monday.