The Spanish second seed, also looking to equal Roger Federer’s men’s record of 20 singles Grand Slam titles, was never bothered on court Philippe Chatrier.
The claycourt master played deep, used his forehand to devastating effect to set up a meeting with Japanese Kei Nishikori or Italian Stefano Travaglia.
After world number 236 McDonald won the second game, Nadal bagged 11 games in a row to move two sets up, and despite some resistance from his opponent early in the third set, he had no trouble improving win-loss record at Roland Garros to 95-2.
“My objective is to play as well as I can. It was a good match for me today. I’m very happy,” said Nadal.
“Then it’s another difficult match. We’ll see, I hope I’ll be at a good level. It’s always special for me to play here in Paris, on court Philippe Chatrier.”
Tenth seed Victoria Azarenka suffered a shock straight-sets defeat by world number 161 Anna Karolina Schmiedlova in the French Open second round.
The Belarusian, 31, reached the US Open final earlier this month but struggled on the clay against Schmiedlova, who won 6-2 6-2.
The Slovak fell in the second set and the trainer was needed to treat her knee, but it did not halt her progress.
Earlier, third seed Elina Svitolina beat Mexican qualifier Renata Zarazua.
The Ukrainian, 26, failed to win a game in the second set but recovered to claim a 6-3 0-6 6-2 victory.
“I was trying to get back into the match,” she said. “I lost my way a bit and was making too many errors.”
Svitolina won her 15th WTA title in Strasbourg last week but is yet to reach a Grand Slam final.
She will face Russian world number 31, Ekaterina Alexandrova, next.
A possible meeting with Serena Williams in the quarter-finals is no longer on the cards after the American 23-time Grand Slam champion withdrew before the second round match with an Achilles injury.
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