Djokovic, who has lost five finals at this Masters 1000 hard-court event in Mason, a suburb of Cincinnati, ran his career record against Mannarino to 4-0 with Wednesday's victory.
Novak Djokovic completed his comeback from elbow surgery by winning for the fourth time.
"I didn't have a great night and wasn't feeling that well for the first set and a half", said Djokovic. 'Though I think age is just a number, but still, most of us, you know, players that were winning most of the big tournaments in the last decade', said Djokovic.
"I think it adds more to the motivation rather than pressure", Djokovic said of being the first to win all nine Masters.
Serbia's Djokovic will next play Bulgarian Grigor Dimitrov, who beat Mischa Zverev 7-6 (7-5) 7-5. "Obviously I didn't have a lot of practices to try to recover, so I had to manage a little bit". Robin Haase beat third-seeded Alexander Zverev 5-7, 6-4, 7-5 for his first victory against a Top 10 opponent since he beat Zverev last November. 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. Djokovic defeated S.Johnson in straight sets (6-4, 7-6), despite a tight affair in the second set.
Earlier on Wednesday, American world number three and 2017 US Open champion Sloane Stephens set up a third-round meeting with Elise Mertens by beating Germany's Tatjana Maria 6-3 6-2. Nothing could separate them in the mid-range and longer points but Novak had the upper hand in the shortest rallies up to four strokes, finding his range after a poor opening set and celebrating a win despite taking a medical timeout and some pills.
The Serbian called for the doctor towards the end of the second set and was given medication for a stomach problem before returning to the court and reeling off six successive games in a 4-6 6-2 6-1 victory.
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.
In the women's section at Cincinnati, defending champion Garbine Muguruza was ousted by Lesia Tsurenko 2-6 6-4 6-4.