The 13-time grand slam champion continued his quest for a maiden Cincinnati title with a 4-6 6-2 6-1 victory.
The 10th-seeded Serb, who has reached the final five times, suffered stomach problems during the match and was tended to by a doctor during the second set.
"Winning it for the fourth time is a blessing.
I didn't have a great night and wasn't feeling that well for the first set and a half", Djokovic said.
The doctor will also attend Djokovic's next couple of matches in OH and he faces either Grigor Dimitrov or Mischa Zverev in the next round. Djokovic is trying to become the first to win all nine ATP Masters 1000 trophies.
"I know from experience it might come very quickly", he said.
"At the end she managed to come back in the third set and play better and found a way to win the match".
"I really want to win this tournament, and I have been trying".
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'I think the top guys are hanging in there, and it's a good mix now that we have - I feel like it's good times for men's tennis', he added.
Croatia's Marin Cilic beat Marius Copil of Romania 6-7 (4-7) 6-4 6-4, while Robin Haase of the Netherlands defeated Germany's Alexander Zverev 5-7 6-4 7-5. He won his first Masters title at the Western & Southern last year without dropping a set, and he's won all four sets this year.
It was Muguruza's first match since her defeat in the Wimbledon second round, where she was also defending her title.
In the women's draw, defending US Open champion Sloane Stephens was untroubled on her way into the third round, defeating German qualifier Tatjana Maria 6-3, 6-2.
"It was a very ugly match, but I'm happy that I fought, even if the level wasn't very high", said Muguruza.
Djokovic, the 10th seed, recovered from losing the opening set as he saw off Frenchman Mannarino 4-6 6-2 6-1 in two hours and six minutes.
The seventh-seeded Spaniard was up 4-2 and serving in the third set when she double faulted to drop the game, a look of disbelief coming across her face after her final serve went long.