The top-seeded Isner beat the eighth-seeded Harrison 5-7, 6-3, 6-4 at Atlantic Station to join Jimmy Connors, John McEnroe, Andre Agassi and Pete Sampras as the only Americans to win an ATP Tour event five or more times.
"I'm very comfortable here,'' said Isner, the 6-foot-10 former University of Georgia star. "I make breakfast in my own room, I go to the Publix next door, it really feels like I'm at home, and that helps so much.''
Isner improved to 31-4 in the event, winning four matches in Atlanta after a 6-hour, 36-minute loss -- with a 26-24 fifth set -- to Kevin Anderson in the Wimbledon semifinals. Isner won three straight titles from 2013-15, and lost the 2016 final to Nick Kyrgios.
Isner has 14 ATP Tour titles, also winning the Miami Open in April.
"I realize I was fortunate today,'' Isner said. "I've been on the other end where you have four or five chances to put your stamp on the match and you don't get it, and I just had one chance, and played a good point, and was able to win the second set, and had one chance in the third and got up early. That's how our sport goes sometimes, and I was very fortunate today.''