Spaniard Muguruza, seeded third in the women’s draw, was beaten in straight sets by Latvia’s Anastasija Sevastova.

The 22-year-old started the better of the two with an early break before the Latvian, ranked at 48 in the world, found her feet on her way to seeing out a surprise 7-5, 6-4 victory.

Canadian Raonic, who came into the last Grand Slam tournament of the year as one of the favourites following his run to the Wimbledon final, appeared to be hampered physically throughout his encounter with American qualifier Ryan Harrison.

The fifth seed, who took the first set, struggled with bouts of cramp and the world number 120 took full advantage, progressing to round three with a 6-7, 7-5, 7-5, 6-1 win.

“It was probably just nerves and stress, a mental sort of over-exuberance," Raonic said.

"Cramping in the left arm, right forearm there towards the end of the third set, both quads, a little bit in the hip flexor on the left.

“It was just catching me all over."

He added: "I couldn't switch grips from one point to the next.

“There were a few points where I would hold the racket with my left hand and trying to stretch out my right hand in between shots."

World number one Novak Djokovic, who has been out of sorts of late following early exits at Wimbledon and the Olympic tournament at Rio 2016, booked his place in the third round after Czech opponent Jiří Veselý withdrew before the match through injury.

Veselý, who beat Djokovic in Monte Carlo in April, was forced to pull out with an inflamed arm and the defending champion will now go on to face Russia's Mikhail Youzhny.

Fourteen-time Grand Slam winner Rafael Nadal comfortably overcame Italian Andreas Seppi 6-0, 7-5, 6-1 under the roof at the Arthur Ashe Stadium.

Croatian Marin Cilic, winner of the US Open in 2014, also safely progressed as he beat Sergiy Stakhovsky of Ukraine 6-1, 6-2, 6-3.

There was another upset in the women’s draw as the unseeded Caroline Wozniacki of Denmark ousted ninth seed Svetlana Kuznetsova 6-4, 6-4.

Seventh seed Roberta Vinci of Italy, who finished as the runner-up last year, swept aside Christina McHale of the United States 6-1, 6-3.