Top seed and defending champion Isner advanced to the quarterfinals at the Hall of Fame Tennis Championships on Wednesday, beating France's Mahut 6-2, 7-6 (2).
The win by Isner featured the two players who played the longest match in tennis history.
Two years ago, the pair played 11 hours, 5 minutes at Wimbledon, with Isner finally getting a 70-68 fifth-set victory.
This one didn't have nearly the drama with the 6-foot-9 Isner using his overpowering serve to take charge. It ended when Mahut double-faulted, ending the match in 1 hour, 18 minutes.
Last year, the pair met again at Wimbledon, with Isner winning in three sets in a match that lasted about two hours.
On Wednesday, playing under bright and sunny late-afternoon skies with a slight breeze and a larger than usual crowd for the time of day, Isner ousted Mahut on Newport's grass court.
"From the moment I warmed up today I knew I was going to play better," said Isner, who struggled in his opening-round match Tuesday. "Getting that first match over yesterday helped a lot -- even though it wasn't the prettiest of matches."
He broke in the first game of the match and again in the third en route to a 4-0 lead. He closed the first set in 31 minutes, getting aces on the final three points.
"If I serve well it makes a big difference in my matches -- no matter how I'm playing in the other facets of the game," he said. "That's a weapon that I'm very fortunate to have."
And that ended a rematch of the pair that played on three different days two years ago.
"Next year's Wimbledon we'll probably see each other," he said, smiling when his news conference ended.
Isner had 13 aces in the match.
Nishikori, ranked 18th in the world and the highest in his country, held a 5-0 lead in the tiebreak before losing the first set. He threw his racket to the ground twice as he headed to his chair for a break.
"It's always tough when you have set point and you lose the set," he said. "I just tried to forget the first set and concentrate on each game. Luckily I got a break in the third game. I was able to keep my fight going."
Querrey was up 5-3 in the second set and had two match points before Sela rallied.