Eighth seed and former world number one Caroline Wozniacki became the biggest casualty of the first round when she crashed out 6-2 6-2 to Romania's Irina-Camelia Begu.
It was another low in a miserable year for the Dane, who also lost in the first round of Wimbledon, but there were extenuating circumstances as she had her right knee heavily taped.
Wozniacki sustained the injury bidding for her fifth straight New Haven title last week and pulled out during her semi-final against Maria Kirilenko.
Kirilenko is one of the form players of the WTA Tour and the 14th seed was an easy winner, 6-2 6-1 over South Africa's Chanelle Scheepers.
Serena Williams was in fine form as she began her US Open campaign with a 6-1 6-1 victory over fellow American Coco Vandeweghe.
The fourth seed went into the tournament as the title favourite and that will certainly not have changed after this performance, although she was not given much of a test.
Venus Williams walked away from the US Open last year with many people questioning whether she would ever be back.
The two-time champion had withdrawn from the tournament and announced she was suffering from the strength-sapping auto-immune disease Sjogren's Syndrome.
The 32-year-old had been on a downward trend and it seemed the end was nigh but, spurred on by the desire to play in a fourth Olympics, Williams pushed herself to play tournaments and slowly she is working her way back to form.
It did not look that way when she succumbed meekly in the first round at Wimbledon, but at the Olympics she was much more like her old self and won a fourth gold medal in the doubles with sister Serena.
Two weeks ago she reached the semi-finals at the Premier tournament in Cincinnati and has now brushed aside fellow American Bethanie Mattek-Sands 6-3 6-1 in the first round on Arthur Ashe Stadium.
Next up for Williams is a big test of her form against sixth seed Angelique Kerber, who has not looked back since her surprise run to the semi-finals here last year.
Kerber brushed aside Britain's Anne Keothavong 6-2 6-0 while second seed and Wimbledon finalist Agnieszka Radwanska eased fears about a shoulder injury with a 6-1 6-1 victory over Russia's Nina Bratchikova.
Fast-rising American Sloane Stephens reached the third round last year and she made a great start with a 6-3 6-4 victory over 22nd seed Francesca Schiavone.
Ana Ivanovic, seeded 12th, saw off Elina Svitolina 6-3 6-2, while there were also wins for Sara Errani, Jelena Jankovic, Dominika Cibulkova and Roberta Vinci but seeds Peng Shuai, Monica Niculescu, Tamira Paszek and Klara Zakopalova crashed out.