Isner fired 15 aces and won over 90 percent of points on his first serve to take the match in an hour and 15 minutes.
The towering American will meet another big-serving giant in South African defending champion Kevin Anderson, who was pushed harder by Taiwan's Yen-Hsun Lu in their 6-4 3-6 6-3 match.
Second-seeded German Tommy Haas had little trouble in beating Uzbek Denis Istomin 6-4 6-1 but third seed Sam Querrey was sent packing by Latvian Ernests Gulbis 6-4 4-6 7-6.
Haas, the 2006 champion, was also strong on serve and wrapped up the match in just 67 minutes.
"It's a little different with the cool weather and no wind today so it was very pleasant to play," Haas told reporters.
"I had a lot of chances early on that I didn't take and frustrated me, but at 4-5 I broke him to win the first set and I think that mentally disturbed him a little bit."
American Querrey crashed out after taking a 4-0 lead in the deciding set, and racked up eight double-faults, including one when serving for the match.
Eighth seed Xavier Malisse of Belgium was also bundled out, losing his rain-interrupted match 7-6 3-6 6-3 to Spanish qualifier Daniel Munoz.
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