Olympic champion Elena Dementieva kicked off her US Open campaign with a 6-4 7-5 win over Akgul Amanmuradova.
The fifth seed struggled against her Ukrainian opponent and had to save two set points in the second set before coming through in one hour 28 minutes.
World number two Jelena Jankovic, who has never reached a Grand Slam singles final, began her campaign by beating wildcard Coco Vandeweghe 6-3 6-1.
Former champion and third seed Svetlana Kuznetsova saw off Zhang Shuai 6-4 6-2.
Lindsay Davenport, the 1998 champion, showed no ill effects from a recent knee injury as she beat Canada's Aleksandra Wozniak 6-4 6-2.
The 32-year-old American was playing her first match since she was forced to pull out of her second-round match at Wimbledon.
"Each time I play a Grand Slam I always think that, 'Oh, this could be my last time playing here'," said Davenport.
"I've obviously learned that I have no idea what the future holds and what will happen, and I don't make decisions for the future any more from this day that I'm living in."
Dementieva, who goes on to face France's Pauline Parmentier, said she was still struggling to put her Beijing victory behind her.
"It's really very hard not to think about the Olympic Games," said the Russian. "It's very difficult to refocus and get ready for the Open.
"Yesterday I was trying to go to sleep but I couldn't because I was watching the closing ceremony and my mind is still there."
Anna Chakvetadze, the 10th seed at Flushing Meadows, suffered her earliest Grand Slam defeat in over three years as she lost 1-6 6-2 6-3 to fellow Russian Ekaterina Makarova.
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