The match was just the second in their 10 meetings in which at least one set didn't go a tiebreaker.
"That one's not the norm for us," said Isner, the runner-up to Rafael Nadal in last year's tournament. "I thought I played well from the very beginning. I was seeing the ball well. From the first warm-up ball, I felt like it was going to be a good night. It helped that Kevin didn't play as well as he normally plays. A lot of things went well."
Fifteenth-seeded Fabio Fognini avoided an upset, pulling out a 6-4, 4-6, 7-6 (5) win over Edouard Roger-Vasselin. Also, Gilles Simon earned a second-round match against top-seeded Novak Djokovic with a 6-3, 6-2 win over qualifier Bernard Tomic.
Three other seeded women who played Monday advanced to the second round. Ninth-seeded Ana Ivanovic came from behind in the second set to beat Sorana Cirstea 6-1, 7-5, while 12th-seeded Caroline Wozniacki dispatched Magdalena Rybarikova 6-2, 6-3 in a match that was interrupted by a late-afternoon storm and 13th-seeded Flavia Pennetta prevailed over qualifer Chanelle Scheepers 6-3, 6-7 (3), 6-2.
Ivanovic won despite dealing with lingering back problems, she said.
"I was happy," she said. "I was a little bit doubtful going on the court considering last few weeks. I had a little bit struggle with my back, but I was able to move free, especially in the first set, and I played well. Also, it was tough playing a good friend of mine. It's never easy. You have to put it aside and try to do the best you can on court."
Keys pulled off a 6-2, 6-4 win over Cornet to advance.
"I don't have many complaints about today," the 19-year-old American said. "I definitely played pretty well and stayed in my game for the most part. There's obviously a couple of things that I still want to work on and have better for next round, but I'm pretty happy with today."
Cornet, who upset the top-ranked Williams in the third round at Wimbledon six weeks ago, was playing with an injured left leg that she said started bothering her during her second-round loss to Victoria Azarenka on Tuesday at the Rogers Cup in Montreal.
"That's not the reason I lost, but it didn't help," said the Frenchwoman, who lost to Keys earlier this year. "She was very aggressive, hitting all winners."
Three qualifiers advanced in other women's first-round action. Taylor Townsend outlasted Klara Koukalova 6-3, 4-6, 7-5, while Pauline Parmentier eliminated Casey Dellacqua 7-6 (4), 6-2 and Karin Knapp upset wild card Belinda Bencic 6-2, 7-6 (1).
Fernando Verdasco needed three sets to eliminate Marcel Granollers 5-7, 6-3, 7-6 (5). Three other players advanced with first career wins over their opponents, led by qualifier Benjamin Becker, whose 7-6 (5), 6-4 upset of Ivo Karlovic was the German's first win in seven matches against the 28th-ranked Croatian. Also, Philipp Kohlschreiber beat Jeremy Chardy 6-3, 4-6, 6-4, the 24th-ranked German's first win in three matches against the Frenchman, and Lu Yen-Hsun advanced with a 6-3, 6-4 win over Denis Istomin, Lu's first win in four matches against Istomin.
Qualifier Marinko Matosevic moved on with a 6-4, 7-6 (4) win over Nicolas Mahut, while Gael Monfils needed three sets to get past 63rd-ranked Federico Delbonis 6-3, 3-6, 6-3. No. 37 Joao Sousa was tested by qualifier Chase Buchanan before prevailing 5-7, 7-6 (3), 7-6 (5), but Jerzy Janowicz easily advanced with a 6-4, 6-4 win over Teymuraz Gabashvili.