Serena Williams' bid for the calendar grand slam got off to the perfect start as the American breezed past Russian Vitalia Diatchenko and saw six seeds in the top half of the draw drop out.
Seventh seed Ana Ivanovic led the list of challengers to fall at the first hurdle but there were also surprise defeats for Karolina Pliskova, Carla Suarez Navarro, Jelena Jankovic, Sloane Stephens and Svetlana Kuznetsova.
Third seed Maria Sharapova, due to meet Williams in the semi-finals, had already withdrawn on Sunday due to injury.
The exits in theory should ease the American's path to the final as she bids to become the first female player in 27 years to win all four majors in a single year.
Williams had little trouble sealing her own place in round two as she won eight consecutive games in just 30 minutes against Diatchenko before her beleaguered opponent retired through injury, trailing 6-0 2-0.
US Open 2015 in pictures
US Open 2015 in pictures
1/4 First Round
Novak Djokovic celebrates his victory over Joao Souza
2/4 First Round
Serena Williams consoles Vitalia Diatchenko after beating her in the US Open
3/4 First Round
Heather Watson suffered an early exit to Lauren Davis in a 7-6 7-6 defeat
4/4 First Round
Kei Nishikori lost to Benoît Paire 6-4 3-6 4-6 7-6 6-4
Diatchenko has struggled with an Achilles problem this year and it appeared to be the cause of her discomfort again as the world number 86 took a medical time-out at 5-0, then a toilet break at the end of the first set, before finally confirming her withdrawal.
The interruptions made for a subdued atmosphere during what was meant to be the main event of day one in Flushing Meadows, as any excitement was also numbed by Williams' total domination.
"It was definitely different and bizarre," said Williams, who will now play Dutch qualifier Kiki Bertens.
"At the same time I was still focused. I kept thinking 'don't lose it'. You never know what can happen."
Williams is bidding to become the first player to win all four grand slams in a single year since Steffi Graf in 1988 and only the fourth female to achieve the feat in history.
Her chances of doing so appear to have improved after a number of rivals bowed out.
Ivanovic, who beat Williams in the 2014 Australian Open, was playing the opening match of the tournament on Arthur Ashe and the home crowd were not made to wait long for an upset as she lost 6-3 3-6 6-3 to Slovakian Dominika Cibulkova.
Cibulkova represented a tough opening test, having reached the Australian Open final only last year before falling down the rankings due to an Achilles injury.
It is the third time this season Ivanovic has been knocked out before the third round at a grand slam.
"It was a very tough match-up I thought, especially for the first round," Ivanovic said.
"I really felt like I had been improving. Last week I saw a huge improvement in my game overall - my serve was really good today.
"That's why it's so disappointing because it was a very tough first match I think for both of us.
"So it's not easy but today I felt like she used her opportunities better than I did."
Pliskova lost to American qualifier Anna Tatishvili, Suarez Navarro was beaten by Czech Denisa Allertova, while Jankovic and Kuznetsova fell to French duo Oceane Dodin and Kristina Mladenovic respectively.
Stephens lost in straight sets to fellow American Coco Vandeweghe.
Serena's sister Venus came close to joining the list of casualties but the 13-time grand slam champion dug deep to beat Monica Puig in three sets.
American Madison Keys and Switzerland's Belinda Bencic are also safely through.