Novak Djokovic and defending champion Marin Cilic took different routes into the fourth round of the US Open while pressure mounted on Serena Williams' quest for a calendar grand slam on Friday.

After two routine wins to open the year's final slam, Williams was given a major fright by Bethanie Mattek-Sands before the 33-year-old American recovered for a 3-6 7-5 6-0 victory.

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 grand slams in a single season, next faces fellow American Madison Keys.

Looking further ahead is a potential quarter-final clash with older sister Venus.

After a week of punishing heat that saw a record 13 players retire, cooler temperatures returned to Flushing Meadows 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) 7-6(1) 6-3 6-7(3) 6-1.

The big-hitting Croat stepped onto the Grandstand court having won 16 straight sets at the National Tennis Center but that string 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. "For sure (being defending champion always has some weight to it.

"Playing on a big court with a full house, that's going to give you some extra motivation in the situations like today when I was a set and 5-2 down."

It had been a trouble-free visit to New York for Djokovic, the top seeded 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."It was a tough three sets."

Frenchman Jeremy Chardy provided the upset of the day dispatching seventh seeded Spaniard David Ferrer 7-6(6) 4-6 6-3 6-1 and was joined at the exit by Canadian 10th seed Milos Raonic who was beat 6-2 7-6(4) 6-3 by Spain's Feliciano Lopez.

Venus Williams, who won the second of her two U.S. Open titles 14 years ago, struck a blow for the older set by taming Swiss teen Belinda Bencic 6-3 6-4.

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

"I just wanted to stay aggressive and keep my errors down," said Venus, who had also beaten Bencic in straight sets in their three previous encounters.

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.