The Englishman carded a closing 68 at Brookline as he finished six under par, one shot ahead of world number one Scottie Scheffler and playing partner Will Zalatoris.
Speaking after his historic victory, the 27-year-old said: "The feeling's out of this world. It is so cliche, but it's stuff you dream of as a kid. To achieve it, I can retire a happy man tomorrow.
"It's what you grow up dreaming of winning and I've worked so hard for such a long time.
"I had the big monkey on my back of not winning over here, it's all everybody talked about and to do it in a major, there's nothing better.
"I don't know if Jack (Nicklaus) is listening to this but he gave me some abuse at the start of the year, when I won a member-member competition at his club and he said congratulations on finally winning in the United States.
"I can go back to him now and say I've won twice."
Thanks to his win, Fitzpatrick joins 18-time major winner Nicklaus as the only two players to have won the US Amateur and the US Open on the same course.
The American famously achieved the feat at Pebble Beach back in 1961 and 1972. Fitzpatrick, on the other hand, won the US Amateur at Brookline back in 2013.
"Any time you're sharing a record with Jack Nicklaus, it's unbelievable," Fitzpatrick added. "So for me to have that as well is incredible.
"He called me up at the presentation to congratulate me. Coming from someone like that, it means the world."
Scheffler and Zalatoris both had chances to take Fitzpatrick to a play-off, but narrowly missed birdie putts on the 18th.
"I battled like crazy," Zalatoris said. "Obviously, you say that about every US Open round you play, but considering where I drove it today, the fact I was even under par was obviously pretty nice.
"I thought I made a lot of nice putts just to keep myself in it. Stealing one on 9, saving par on 13. I really felt great with the putter all week, and I hit a great putt on 18. It just happened to hang out there.
"It was fun, man. Matt's shot on 18 (from the fairway bunker) is going to be shown probably for the rest of US Open history.
"I walked by it, and I thought that going for it was going to be ballsy, but the fact that he pulled it off and even had a birdie look was just incredible. So hat's off to him."