Serena Williams flirted with Grand Slam danger once again but kept her calendar-year major bid on track by beating a battling, 101st-ranked Bethanie Mattek-Sands 3-6, 7-5, 6-0 at the 2015 US Open on Friday.

Serena, who lost nine sets, including seven first-set losses, in her charge to the Australian, French and Wimbledon titles, was tested at Flushing Meadows by her fellow American, but roared back to victory to reach the fourth round.

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"I'm not trying to live on the edge," the 33-year-old Serena said in an on-court interview. "I'm playing players that come out really strong. I just think Bethanie played really well."

The world number one looked out of sorts at the start, broken twice in dropping the first set to the aggressive Mattek-Sands, who at age 30 still looks like a punk rocker with a splash of orange topping her pinned up blond hair.

Serena at times appeared to be trying too hard, putting extra effort into opportunities to produce a service break and often overhitting and sending shots wide or long.

She won only one of seven break points in the first set, and two of nine in the second.

A service break by Serena in the last game of the second set, on her second set point, forced the decider and by then Serena seemed to have relaxed and produced the prodigious power that has carried her to a 51-2 record this year.

"She's a great player. She's fought so many difficult injuries," Serena said of Mattek-Sands. "I respect her a lot and know to expect a great game."

The 21-times Grand Slam singles winner, who is aiming to join Maureen Connolly (1953), Margaret Court (1970) and Steffi Graf (1988) as the only women to sweep the four majors in a single season, next faces fellow American Madison Keys.

Keys advanced 6-3, 6-2 over 15th seed Agnieszka Radwanska of Poland.

In the men's singles, top seed Novak Djokovic and defending champion Marin Cilic took different routes into the fourth round of the US Open as the upsets and searing heat at Flushing Meadows both eased off on Friday.

After a week of punishing heat that saw a record 13 players retire, cooler temperatures and order returned to the year's final grand slam as world number one Djokovic eased to a third round 6-3, 7-5, 7-5 victory over Italian Andreas Seppi.

Cilic also kept his title defence on track but not without a scare as the ninth seed needed over four hours to put away Kazakhstan's 56th-ranked Mikhail Kukushkin 6-7 (5-7), 7-6 (7-1), 6-3, 6-7 (3-7), 6-1.

The big-hitting Croat stepped onto the Grandstand court having won 16 straight sets at the National Tennis Center, but that streak quickly came to an end when Kukushkin took the opening set in a tiebreak in what was the start of a long and harrowing afternoon for the defending champion.

"I'm happy with the fighting spirit today, just accepting that I wasn't playing so well," said Cilic.

It had been a trouble-free visit to New York for Djokovic, the lanky Serb not dropping a set while losing just 10 games going into his match against Seppi.

But the 25th-ranked Italian at least made Djokovic work for his spot in the round of 16, the world number one needing a tiring two and a half hours at Arthur Ashe Stadium to secure his victory.

"Just hanging in there, trying to create my own pace and control the rallies," Djokovic said about dealing with the capable and aggressive game of Seppi. "It was a tough three sets."

Elsewhere, Venus Williams, who won the second of her two US Open titles 14 years ago, struck a blow for the older set and stayed on course for a quarterfinals collision with Grand Slam-seeking sister Serena by taming Swiss teen Belinda Bencic 6-3, 6-4.

Venus, 35, produced a vintage power-game performance to beat the up-and-coming 18-year-old in a match-up between the oldest and youngest players left in the women's draw.

Joining the seven-times Grand Slam singles winner in the fourth round was Russian 13th seed Ekaterina Makarova, who advanced with 6-3, 7-5 victory over 17th seed Elina Svitolina of Ukraine.