The 6-foot-9 Isner served 13 aces in the match that lasted just 59 minutes on Newport's grass courts.
It was a Wimbledon rematch for the pair. Isner retired in the third game of the previous match last month after injuring his left knee.
The No. 2 seeded Isner needed only 15 minutes to win the opening set, and served four aces in the second-set tiebreak. He closed it out when Mannarino hit a forehand wide off a 131 mph serve.
It was Isner's 12th consecutive win at Newport.
On Friday, Isner will face fellow big server Ivo Karlovic, who defeated Canadian Vasek Pospisil, in three sets. This will be the fourth meeting, and the first on grass courts, between Isner and Karlovic, who are the two tallest players on the ATP World Tour. Karlovic leads the head-to-head 2-1.
"This certainly could be a match that can come down to just a point here and there," said Isner.