Novak Djokovic has likened his U.S. Open quarter-final opponent Matteo Berrettini to a "hammer" but the top-ranked Serb heads into Wednesday's clash with all the tools to dismantle the big-serving Italian and stay on course for a 21st Grand Slam title.

The two players face off in a rematch of the Wimbledon final which Djokovic won to go level with Roger Federer and Rafa Nadal on 20 majors but not before enduring a scare from his 25-year-old rival who possesses a blockbuster serve and forehand.

"Next to Juan Martin del Potro, he's probably the hardest hitter of serve and forehand. He's got the lethal-serve-plus-one game," Djokovic, who also beat Berrettini in the Roland Garros quarter-finals and in the 2019 ATP Finals, said.

"He's already established as a top player. Without a doubt, he played... the semi-finals here couple years ago, finals in Wimbledon. That was a tough four-setter."

A New York triumph will mean Djokovic will become only the third man, and the first since Rod Laver in 1969, to hold all four majors in the same year having won the Australian Open, French Open and Wimbledon titles in 2021.

Despite struggling to click into gear early in some of his matches, the relentless 34-year-old has scrapped his way past tricky opponents this year and will be the firm favorite to advance but Djokovic is not taking Berrettini lightly.

"Look, if he serves well, which is his biggest weapon, he's tough. He's tough on any surface to play against. I've had some really close matches with him in the French Open and Wimbledon recently," Djokovic said.

"We're going to play the third slam in a row against each other. Hopefully the result will be the same as the previous two."

Fourth seed Alexander Zverev has hardly been troubled at Flushing Meadows this year and the German will be in action against South African Lloyd Harris in the day's other men's quarter-final.

Among the women, fourth seed and former world number one Karolina Pliskova, who like Zverev is also chasing a first major title, meets dark horse Maria Sakkari in a highly anticipated match during the evening session on Arthur Ashe Stadium.

British 18-year-old Emma Raducanu, who is among a handful of teenagers making their breakthrough at this year's tournament, will look to continue her dream run but faces a potentially daunting challenge against Olympic champion Belinda Bencic.