World number 35 Isner was dominant on his first serve, winning 6-4 6-7 (3-7) 6-4 to claim a spot in the second round where he will face Jack Sock, who beat Ricardas Berankis in three.
Isner's 36 aces equaled the previous Atlanta Open record set by Sam Querrey in his three-set win over Peter Gojowczyk a day earlier.
American fifth seed Taylor Fritz also progressed with a 6-3 6-4 victory over Russian Evgeny Donskoy.
French seventh seed Benoit Paire got past Japan's Yasutaka Uchiyama 7-5 6-7 (2-7) 6-4, while enigmatic Australian Nick Kyrgios beat South African Kevin Anderson 7-6 (7-4) 6-3.
Teenage American talent Brandon Nakashima knocked out Trent Bryde, while Australian Chris O'Connell beat Denis Kudla and Finland's Emil Ruusuvuori got past Mackenzie McDonald 7-6 (7-3) 7-5.
Nakashima, who got a special exemption entry into the Atlanta Open, next takes on top seed Milos Raonic.