American qualifier Ryan Harrison has pulled off the biggest upset so far at the ongoing US Open, stunning fifth-seeded Canadian Milos Raonic 6-7 (4-7), 7-5, 7-5, 6-1 in second-round tennis action.

Raonic appeared to be in total control when he went up a break in the third set, but leg cramps began severely hampering his movement and allowed Harrison to climb back into the match on Wednesday, reports Efe.

The 120th-ranked American closed out the third set and then rolled to an easy victory in the fourth against his hobbled opponent.

Raonic, one of the best servers on the ATP Tour, struck 18 aces but also committed a whopping 15 double-faults. Harrison managed to win the match despite 12 double-faults over the course of the contest.

The Canadian said afterward that he started cramping midway through the second set, blaming "nerves and stress".

The result is a major disappointment for Raonic, who reached the Wimbledon final earlier this summer and was considered by many pundits to be one of the top three contenders for the US Open title along with Serbian world No.1 Novak Djokovic and British world No.2 Andy Murray.

Earlier, Djokovic advanced to the third round by walkover when his opponent, Czech Jiri Vesely, withdrew from the tournament with a left forearm injury.

In other men’s results, mercurial Frenchman Gael Monfils, the No.10 seed, continued to showcase a more mature on-court attitude in a 7-5, 6-4, 6-3 victory over Czech Jan Satral.

Monfils had been placed in Raonic’s section of the draw and stands to benefit from his early exit from the tournament, as could Spanish No.4 seed Rafael Nadal.

In a mild upset in the women’s draw, Denmark’s Caroline Wozniacki, a former world No.1 and the 2009 and 2014 US Open finalist, defeated 2004 champion Svetlana Kuznetsova of Russia, the No.9 seed 6-4, 6-4.