The two-time Wimbledon champion toiled for more than two and a half hours against world number 80 McDonald, eventually taking the match 3-6 6-4 7-5, just his second win of an injury-interrupted year.
Murray, playing for the first time since pulling out of Wimbledon, converted his seventh match point to clinch a three-set victory and set up a meeting with fellow Briton Kyle Edmund in the second round in Washington DC.
Murray's first hardcourt match in almost 17 months, delayed three hours by rain, turned when he broke in the penultimate game of the second set and again on his fifth break chance in the opening game of the third set.
Murray's first hardcourt match in almost 17 months turned when he broke in the penultimate game of the second set and again on his fifth break chance in the opening game of the third set.
He looked in trouble but found new life when McDonald sent a forehand wide to hand Murray a break and a 5-4 advantage in the second set.
Particularly when he was failing to convert any of the five match points he held while serving for the win at 5-4 in the final set.
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At 30-30 in the 11th game, McDonald stuck his racquet over the net to play the ball, losing the point on a violation quickly called by French umpire Arnaud Gabas.
His lone win on grasscourts came over Swiss Stan Wawrinka, another three-time Grand Slam victor fighting back from injury.
The 31-year-old was speaking at a press conference ahead of his return to competitive action at the Citi Open in Washington D.C.
Andy Murray says he feels like he is starting from scratch as he attempts to climb back up the rankings following his comeback from hip surgery.
His lone win on grasscourts came over Swiss Stan Wawrinka, another three-time Grand Slam victor fighting back from a left knee injury. "Maybe tennis could do a better job of being a bit more transparent with that and kind of showing exactly how many tests everyone has had".
"I made a few less mistakes, but I would like to play better tennis in the next match".