The 27-year-old is the third Englishman in 52 years to have won the second-oldest major in golf, and joins Jack Nicklaus as the only player to win the US Amateur and the US Open on the same course.
Fitzpatrick won the US Amateur at Brookline in 2013 during a season which also saw Justin Rose become the last Englishman to claim the US Open title at Merion.
The world number 10 found himself a shot behind Zalatoris with six holes remaining, before producing a birdie from 50 feet across the 13th green to draw level. Two holes later, he moved two shots clear after firing in yet another birdie.
His best shot was saved for last, as Fitzpatrick produced a stunning effort from a fairway bunker on the 18th to mark his first major win in scintillating style.
Current world number one Scottie Scheffler was never far off and closed the gap to just one shot with a birdie of his own on the 17th. Zalatoris followed suit on the 16th, but the American was unable to convert from 14 feet on the 18th to force a play-off.
With his brother on the bag, Fitzpatrick contested the closing round from the final group for the second successive major.
The player had already partnered Mito Pereira during the US PGA finale at Southern Hills last month.
On that occasion, a closing score of 73 meant the Sheffield-born golfer missed out on a play-off between Zalatoris and Justin Thomas by an agonising two shots. Thomas went on to bag his second US PGA title in a three-hole shootout.
Former Masters champion Hideki Matsuyama finished the day with a 65, making it the lowest round of the week. The Japanese golfer sealed fourth place with that impressive final round display.
Rory McIlroy and Open champion Collin Morikawa shared fifth on two under par.
McIlroy is still searching for his first major since 2014 and could've been in the hunt on Sunday if not for a disastrous third-round showing which saw a mix of four birdies and four bogeys in his first 14 holes.
Meanwhile, defending champion Jon Rahm started Sunday's finale just a shot off the lead, but struggled to a closing 74.