Djokovic, Murray sail on as Serena stands up for America
Serena Williams of the US reacts to a point against Varvara Lepchenko of the US during their 2014 US Open women's singles match at the USTA Billie Jean King National Tennis Center on August 30, 2014 in New York - by Stan Honda
But as the heavyweights of the sport eased into the fourth round, the women's draw was blown open again when Wimbledon champion Petra Kvitova became the fifth top 10 seed to exit in the first week.
Kvitova's misery was shared by American tennis after John Isner and Sam Querrey were both knocked out in the third round leaving the hosts still without a men's Grand Slam champion since Andy Roddick triumphed in New York in 2003.
Djokovic, the 2011 champion, brushed aside Querrey for the eighth time in nine meetings, with a 6-3, 6-2, 6-2 win taking the world number one into the fourth round at a major for the 22nd consecutive time.
"Sam is big server, very powerful. But he doesn't move that well so I wanted to keep him moving around the court, mix up the pace and get as many returns as possible back," said Djokovic after an 85-minute win which was never in doubt from the time he raced into a 5-0 lead in the first set.
Wimbledon champion and seven-time major winner Djokovic will next face Germany's Philipp Kohlschreiber who ended US hopes with a 7-6 (7/4), 4-6, 7-6 (7/2), 7-6 (7/4) win over Isner despite the American 13th seed firing 42 aces and 77 winners.
It was the third successive year that Kohlschreiber had defeated Isner in the third round.
"It's a disappointment for me personally, not the United States as a whole," said Isner.
Williams racked up her 75th victory at the US Open when she eased past her third successive American compatriot, Uzbekistan-born left-hander Varvara Lepchenko, 6-3, 6-3 and will tackle tough Estonian Kaia Kanepi for a quarter-final berth.
"I had to make some adjustments because of the wind but I got some excellent advice from my coach," said 32-year-old Williams, playing in her 15th US Open and aiming to become just the second woman after Chris Evert in the 1970s to win three New York titles in succession.
"My opponent played at an unbelievable level but I tried to hang in there and do what I needed to do."
Murray, the 2012 champion, hit 47 winners in a 6-1, 7-5, 4-6, 6-2 victory over Russia's Andrey Kuznetsov, the world 96, to book a seventh appearance in the fourth round and goes on to face French ninth seed Jo-Wilfried Tsonga who beat Pablo Carreno-Busta of Spain, 6-4, 6-4, 6-4.
"I got off to a good start and then had a cushion when he got back into the match in the third set," said 27-year-old Murray.
- Wawrinka gets walkover -
Third seeded Stan Wawrinka, the Australian Open champion, reached the fourth round without hitting a ball when Slovenian opponent Blaz Kavcic withdrew with a right foot injury.
That took the number of retirements and walkovers at this year's US Open to 10 in the men's event and two in the women's.
Wawrinka next faces either 16th-seeded Spaniard Tommy Robredo or Australian Nick Kyrgios, who shocked Rafael Nadal in the fourth round at Wimbledon.
Women's third seeded Kvitova lost her third round tie 6-4, 6-4 to pint-sized Serbian, 21-year-old Aleksandra Krunic, who came through qualifying.
Kvitova joins second seed Simona Halep, fourth-seeded Agnieszka Radwanska, Angelique Kerber, the sixth seed, and eighth-seeded Ana Ivanovic in failing to make the fourth round.
The 24-year-old Kvitova dropped serve five times and committed 34 unforced errors against the 5ft 4in (1.63m) Krunic who divides her time between the pro tour and studying for a university economics degree.
"It was an honour to play on the same court as Petra, she's a great champion. I watched both her wins at Wimbledon," said Krunic, who next plays former world number one Victoria Azarenka, the runner-up to Williams in the last two years.
Kvitova said she was taken by surprise by her opponent's poise and power.
"I didn't really expect how she played so well. Suddenly she just pushed the ball very hard," said the Czech.
Also going through to the last-16 of the men's singles for a third successive year was Canadian fifth seed Milos Raonic who beat Victor Estrella Burgos, the 34-year-old tournament debutant from the Dominican Republic, 7-6 (7/5), 7-6 (7/5), 7-6 (7/3).
He will face Japanese 10th seed Kei Nishikori who reached the fourth round for the first time since his 2008 debut with a 6-4, 6-2, 6-3 victory over Leonardo Mayer of Argentina.