In hot but not overwhelming conditions, the eighth-seeded Scot was convulsing at times in the third and fourth sets but somehow managed to beat Dutchman Robin Haase 6-3 7-6 (6) 1-6 7-5 at Flushing Meadows.
Renowned as one of the fittest players on the ATP Tour, Murray arrived in New York raving about his mid-season fitness programme in Florida with new coach Amelie Mauresmo.
Finally free of pain, almost a year after back surgery, Murray looked lean and strong as he took to the court and though his tennis was patchy, his movement was good as he took the first two sets.
But from 2-1 in the third set, it was obvious something was wrong and as he cramped up, Haase took advantage to take the third set and lead 5-3 in the fourth.
Moving slightly better but still nowhere near 100 percent, Murray sliced and diced his way back to 5-5 and as Haase faltered, he clinched a dramatic victory.
Murray's next match is against Germany's Matthias Bachinger.
WHAT MURRAY HAD TO SAY
"I felt extremely good before the match, and I did train very, very hard to get ready for the tournament. For me it was unexpected, and therefore, quite difficult mentally to deal with ... especially after an hour and 40 minutes. The fact that it was the whole body would suggest that maybe it was something to do with my eating or drinking, because if it's through fatigue in one part of your body, then that would probably be down to conditioning. But cramping in my left forearm? I didn't use my left forearm a whole lot today compared with other parts of my body, so I would expect it would be something to do with what I have eaten or something or not eaten.
"I'm happy ... because I could have easily lost that match. I was very close to losing the match. I certainly wouldn't have been the favourite if it had gone to five sets. I'm happy about that. Maybe I will speak to a nutritionist and look at what I had eaten the last three, four days. These (Grand) Slams are physically challenging, but I need to work out why that happened because I shouldn't be cramping after one hour, 45 minutes, regardless of the temperature. It was hot but it wasn't particularly humid and we didn't play a lot of long rallies."
It's been a funny old season for Murray, who lost his coach and a lot of his form after an operation to correct a long-standing back problem.
Former coach Ivan Lendl helped the Scot get the Grand Slam monkey off his back, proving that Murray's previous issues were more mental than technical.
But his body has let him down, and suffering cramps and strains so early in his favourite Grand Slam will be of concern.
In mitigation he was on fairly early, having to play in the heat and humidity of a New York summer. And, with Haase serving for the fourth set, Murray's resolve was tested to the full and he will be pleased to have avoided a major upset.
In theory, he should have a better time of it in the second round -next up is Germany's Matthias Bachinger, who surprisingly beat Radek Stepanek 6-3 6-2 6-2.
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