The Irishman, who began the final round at Saucon Valley Country Club in Bethlehem, Pennsylvania with a five-stroke cushion, won by a shot from 2019 champion Steve Stricker.
Harrington was the third consecutive player to win this event in his first appearance, while it is the first time in 25 years that the three US Opens were won by non-Americans.
Australian Minjee Lee and Englishman Matthew Fizpatrick had already come out on top in the US Women’s Open and US Open respectively in recent weeks.
Harrington carded a closing one-over-par 72 for a 72-hole total of 10-under 274 to become the first player from the Republic of Ireland to hoist the Francis D. Ouimet Memorial Trophy.
He also joined World Golf Hall of Famers Arnold Palmer, Gary Player, Lee Trevino and Jack Nicklaus as the only multiple winners of The Open to also win the US Senior Open.
Harrington sealed his victory by holing a 30-foot birdie putt on the par-4 15th hole before closing with three solid two-putt pars.
“I think it's special for me to win this one just because I've never won a USGA event,” said Harrington, who finished second to Stricker in the season’s first senior major, the Regions Tradition, in May.
“I think that adds more than if you could turn around and win a different senior major. But because I was never a US Open champion or a junior champion, it's great to come and win the senior one. It adds something that I never had in my career.”
Stricker captained the US side to victory over the European side led by Harrington last September in the Ryder Cup at Whistling Straits.
“Hats off to him,” said a gracious runner-up. “He played great. It was close, but he was the better player this week.”
Harrington now takes a break from the seniors’ circuit for the next three weeks to play in the Horizon Irish Open, Genesis Scottish Open and The Open.
He will then be back in over-50s action when making his debut in The Senior Open Presented by Rolex at Glenaegles.