Playing his first singles grand slam match since the 2019 Australian Open due to hip surgery and the coronavirus pandemic, Murray looked to be down and out when Nishioka raced into a two-set lead on Wednesday (AEST).

Yet three-time slam champion Murray rallied to a stunning 4-6 4-6 7-6 (7-5) 7-6 (7-4) 6-4 triumph behind closed doors at Flushing Meadows in New York.

Two tie-breaks went Murray's way in sets three and four, and a four-hour 39-minute epic was settled when a trademark lob from the Scot forced Nishioka into an overhit return.

"I'm tired. My toes are the worst part I think, the big toes are pretty beat up, but I did alright," Murray – who will face Felix Auger-Aliassime or Thiago Monteiro in round two – said afterwards.

"At the beginning of the match I was apprehensive about playing a long match, I was kind of pacing myself. I felt a bit like that at the start, but once I was two sets down I had to start putting the afterburners on.

"They have [one ice bath] in the locker room, but they say it's for emergencies. It's an emergency for me right now! I'll ask if I can use that now, but if not I'll have to get back to the hotel quickly and recover because that's by far the most tennis I've played since the 2019 Australia Open."

After a composed start from both players, it was Nishioka who forced the first break to take a 4-3 lead, and the 24-year-old claimed the set at the second attempt three games later.

Japan's Nishioka hardly looked back and had the second set tied up in 53 minutes to put himself in complete control against the 2012 US Open winner.

Murray's fight seemed to have drained when he conceded serve in game one of the next set – Nishioka moving into a 3-1 lead.

Yet the 33-year-old Murray, who underwent hip resurfacing surgery last year, found a second wind, and a break brought him level at 3-3.

Nishioka squandered four break points as a tie-break was required, and Murray made his opponent pay – the former hitting a stray backhand into the net.

Both players held serve in a tense fourth set, but Nishioka had the win within his grasp when he won five successive points at 6-5.

But Murray once more rallied, forcing a long return from Nishioka before two successive points teed up another tie-break.

Murray raced ahead and though an issue with his right foot threatened to derail his display, the eight-time slam runner-up fought through the pain to take the set.

Nishioka clinched the initiative with the first break of the decider courtesy of a double fault, only for Murray to respond immediately with an exquisitely lofted backhand.

A misjudged lob from Nishioka moved Murray to within a game of an incredible triumph – one which was sealed by another delicate lob.