Djokovic has struggled to find his best form following his success at Wimbledon last month and he started slowly against Mannarino.
The Serbian was broken once in the opening set as he was downed 6-4.
Mannarino also earned an early break in the second set but Djokovic recovered to surge into a 5-2 lead before he called for a medical timeout.
Djokovic was struggling with a stomach problem but the doctor attended his court-side seat and the former world No 1 swallowed some pills.
He then returned to the court to wrap up the second set before surging into a five-love lead in the third.
Mannarino was able to hold serve in the sixth game but Djokovic then served for the match.
Djokovic will play the winner of Misha Zverev and Grigor Dimitrov in the next round.
The 31-year-old is hoping to become the first player to win all nine Masters events this week as part of his US Open preparations.
Djokovic only needs the Cincinnati Masters title to secure his Golden masters dream.
Roger Federer has also won eight of the nine Masters titles, with just a win in Monte Carlo needed to complete the set.
World No 1 Rafael Nadal is a Miami and Paris victory away from securing all nine, while Andy Murray also needs two – at Indian Wells and Monte Carlo.
Djokovic looks the more likely to win the event after he picked up his 13th Grand Slam title at Wimbledon last month.
Source : EXPRESS