Five-time champion Roger Federer crashed out of the US Open on Monday, stunned by 55th-ranked Australian John Millman who booked a quarter-final clash with Serbian star Novak Djokovic. 

Millman's 3-6, 7-5, 7-6 (9/7), 7-6 (7/3) triumph scuppered a blockbuster last-four meeting between Federer and two-time US Open champion Djokovic, who had advanced with a 6-3, 6-4, 6-3 victory over Joao Sousa. 

But Federer suffered his earliest US Open exit since he fell in straight sets to Tommy Robredo in the fourth round in 2013. It was also 20-time major winner Federer's first loss against a player outside the top 50 in 41 meetings at the US Open. "I'm probably in a little bit of disbelief," Millman, 29, said after three hours and 35 minutes in the cauldron of Arthur Ashe Stadium.

"Today he was definitely not at his best," Millman said. "But I'll take it." And he'll face another hero in Djokovic for a place in the semi-finals, trying to become the first Australian man to win a Grand Slam since Lleyton Hewitt won Wimbledon in 2002.

Elsewhere, Kei Nishikori, runner-up in 2014, was also pleased to get through in three sets in blazing sunshine on Louis Armstrong Stadium. After racing through the first two sets against Germany's Philipp Kohlschreiber, he dropped his serve while serving for the match at 5-4 in the third, but managed to prevail 6-3, 6-2, 7-5. 

Nishikori will fight for a semi-final berth against Croatian Marin Cilic, who beat him in the 2014 final. That remains Nishikori's best Grand Slam showing. After reaching a career-high fourth in the world in 2015, he slid down the rankings as a wrist injury sidelined him for six months, keeping him out of last year's US Open and this year's Australian Open. 

Seventh-seeded Cilic, who needed eight match points in a five-set marathon against Australian teenager Alex de Minaur spilled into Sunday morning survived some tense moments to get past 10th-ranked Belgian David Goffin 7-6 (8/6), 6-2, 6-4. Goffin served for the first set at 5-4 before Cilic went on to win the tiebreaker. From there, things got easier, but Cilic still needed a third match point to clinch it.

Meanwhile, in the women’s draw, 2006 winner, Maria Sharapova was defeated by Spain's Carla Suarez Navarro in straight sets 6-4, 6-3 in the fourth round. 

The Russian entered the contest hoping to continue her search for a first Grand Slam title since returning from a doping ban in April last year, but the quest goes on after her first loss under the lights at Flushing Meadows. 

Sharapova, who won the last of her five Slams at Roland Garros in 2014, has endured a disappointing return to the majors since the end of her drugs ban. Suarez Navarro will celebrate her 30th birthday on Monday.

Sharapova had been 22 matches undefeated under the lights in Arthur Ashe Stadium. The Spaniard 30th seed will face 2017 runner-up Madison Keys in a bid to reach her first Grand Slam semi-final.

Japanese 20th seed Naomi Osaka registered 6-3, 2-6, 6-4 win over the 26th seeded Aryna Sabalenka of Belarus for a quarter-final place. Osaka is the first woman from her country to reach a Grand Slam's last eight since 2004.

And 14th seed Madison Keys defeats 29th seed Dominika Cibulkova 6-1, 6-3 to progress to the quarter-finals. Last year's runner-up plays a match which includes six aces, and no double-faults, in her best performance of the tournament.