The 27-year-old ended up winning at Brookline by a stroke over USA's Will Zalatoris, who missed a jump-off after missing a putt on the last hole by a hair's breadth.
World number one Scottie Scheffler also tied for second place after a round of 67 on Sunday.
Fitzpatrick completed the four rounds of the par-70 course at the Country Club outside of Boston in 274 strokes.
It was also his first win ever on the PGA Tour.
"It's something I've worked for so long, for so long," Fitzpatrick said at the awards ceremony.
"To do that, my first win, a Major - it doesn't get any better than that." Only the second golfer after the great Jack Nicklaus, Fitzpatrick won both the amateur title (2013) and the US Open on the same golf course.
Close fight up to the 18th hole
Fitzpatrick and Zalatoris started lap four in the lead together and fought an exciting duel to the end, with Scheffler a lane ahead as an added factor.
When Fitzpatrick bunkered the tee shot at hole 18, Zalatoris seemed to have the advantage.
The Englishman saved himself with a strong shot onto the green, but then missed a possible birdie there.
However, Zalatoris was not able to use the assist and pushed his ball just wide from about four meters.
Two-time Major winner Collin Morikawa from the USA, who had led the field after two rounds and after a round of 77 on Saturday dropped back to shared 17th place, moved up to at least the middle with a round of 66 at the end shared fifth place with Northern Ireland's Rory McIlroy.
Only Hideki Matsuyama from Japan played better on Sunday, finishing fourth after the round of 65.
The two German golfers Yannik Paul and Marcel Schneider clearly failed at the cut after two rounds on their first appearance in a major tournament and were eliminated early.