The 6-foot-9 Isner rode his big serve to win his 11th straight match on Newport's grass-courts.
He was not broken in the match that lasted 1 hour, 20 minutes, taking control by blanking Harrison in the tiebreaker.
Isner, seeded second, broke in the third and seventh games of the second set before Harrison hit a backhand return long on the match's final point.
The 28-year old Isner showed no effects from a left knee injury that forced him to retire from his second-round match at Wimbledon.
In winning the 2012 title in Newport, Isner held serve in 57 of the 58 games he played.
It was a similar formula on Monday.
"Just getting the first one out of the way is critical for me," he said. "I was happy how I played in the second set, took care of my serve well. I felt like I was in a lot of his service games, especially in that second set."
When it was over, Isner let out a loud "Yes!" as Harrison's shot sailed long under sun-drenched skies with temperatures in the low 80s with a slight breeze.
"I remember last year in my first round here, I won 6-4 in the third," said Isner, ranked 19th overall entering the week. " It's always a tough match. Playing Ryan, I beat him here in the semi-finals last year. He's a good grass-court player and he's a friend of mine. But he's someone I don't want to lose to. It's important to win those matches like that. I'm one of the top ranked Americans and I want to continue to stay way for as long as I can, and beating guys like Ryan helps."
Top seed Sam Querrey is slated to face fellow-American Tim Smyczek is his first-round match on Tuesday.
In the most interesting match of the day, Poland's Michal Przysiezny beat 15-year old American Stefan Kozlov, who was making his ATP debut, 6-3, 6-7 (9), 6-4 in a match that lasted nearly 2 1/2 hours.
Kozlov, who lives in the Miami-area, broke to go up 4-3 in the third before calling for the trainer, who worked on his right hip.
"I slipped in the first set on my hip and it kind of got progressively worse," Kozlov said.
The match ended with the youngster limping before falling to the ground as he made his way to the net. He sat in his chair for a while with a towel over his head before slowly walking off the court.
"I was hanging in there and started cramping," he said. "It's kind of tough to play when you're cramping. Now I know I could actually win. I couldn't believe I could win a set."
The tournament is held in conjunction with induction ceremonies into the International Tennis Hall of Fame. Martina Hingis leads the 2013 class that will be enshrined on Saturday before the semifinals.
In other first-round play, Ante Pavic of Croatia defeated Australian John-Patrick Smith 4-6, 6-3, 7-6 (3); Adrien Bossel of Switzerland ousted Canadian Erik Chvojka 2-6, 7-6 (8), 6-4; American Alex Kuznetsov rallied to beat Farrukh Dustov of Uzbekistan 6-7 (6), 7-6 (4), 6-2; Jan Hernych of the Czech Republic beat Ilija Bozoljac of Serbia 6-7 (14), 7-5, 6-2.