The 6-foot 9-inch Isner closed out the match Wednesday with his 11th ace and won 80 percent of his first-serve points.
Isner entered the tournament when defending champion Mardy Fish withdrew after he was selected for the U.S. Davis Cup team. The 26-year old Isner will face fellow American Alex Bogomolov in the semifinals.
Bogomolov ovecame a rough start, downing Ruben Bemelmans, 2-6, 6-0, 6-1.
A No. 1 seed has never won the title in the 35 years of the tournament, played on grass courts.