Isner - a native of nearby Greensboro - hammered down 17 aces, 10 of them coming in a tight first set that had to be settled by a tie-break.
The second was much more one-sided though, the fourth-seeded American recording two breaks of serve to set up a third-round clash with either Denis Istomin or 13th-seeded Jarkko Nieminen.
some other big names weren't so fortunate on Tuesday; Dmitry Tursunov - the 11th seed in the tournament - letting slip a one-set advantage to lose 3-6 6-1 6-3 against Belgium's Steve Darcis.
Igor Kunitsyn also suffered an early exit in the final warm-up before the US Open, the 16th seed going down 6-3 6-1 to French qualifier Julien Benneteau.
The other seed to fall was the 12th-ranked Pablo Andujar, Kei Nishikori of Japan recording a 7-6 (7-3) 6-2 triumph over the Spaniard.
There was better news for fifth seed Nikolay Davydenko, a 6-2 6-2 winner over American Michael Russell, and Juan Monaco, the seventh seed seeing off Tobias Kamke 7-5, 6-0.
The 10th-seeded Robin Haase also progressed at the expense of American James Blake 6-4, 6-1, while Blake's compatriot Donald Young was beaten by Grigor Dimitrov in three sets.