McIlroy felt he was just one great round from claiming a fifth major title and first since 2014 following a battling 73 on Saturday, but mixed four birdies and four bogeys in 14 holes on Sunday to effectively end his chances.
Fitzpatrick had holed from seven feet on the third and two-putted the short par-four fifth for birdie after driving the green on a hole which cost both McIlroy and defending champion Jon Rahm a shot.
The 27-year-old from Sheffield then three-putted the sixth from long range to drop his first shot of the day, but his increased length off the tee paid off again on the par-five eighth as he hit the green in two to set up an easy birdie.
That took him back into a share of the lead and he soon led on his own as Scheffler dropped his first shot of the day on the 10th and then three-putted the 108-yard 11th – the hole which cost him a double bogey in round three.
Zalatoris had almost holed his approach to the seventh and also birdied the ninth to close within a shot of playing partner Fitzpatrick, who surprisingly missed from four feet for par on the 10th after splashing out of a bunker.
A birdie on the 11th took Zalatoris into the outright lead for the first time and moments later he had a two-shot lead, Fitzpatrick three-putting from just a few inches closer to the hole on an identical line.
However, Zalatoris bogeyed the 12th and saw his lead wiped out in spectacular fashion on the next, Fitzpatrick letting out a massive roar after holing from 50 feet across the green for an unlikely birdie.
Fitzpatrick was playing in the final group for the second major in succession, having partnered Mito Pereira in last month’s US PGA Championship at Southern Hills.
— Golf Channel (@GolfChannel) June 19, 2022
A closing 73 meant Fitzpatrick missed out on the play-off by two shots, but the Englishman has been buoyed all week by the memories of his US Amateur victory at Brookline in 2013, the same year Justin Rose became the last English winner of the US Open at Merion.
A victory on Sunday would see Fitzpatrick join Jack Nicklaus as the only players to win the US Amateur and US Open on the same course, Nicklaus doing so at Pebble Beach in 1961 and 1972.
All three previous US Opens held at Brookline ended in a play-off and tournament officials had made reference to two of those on the final two holes.
The pin position on the 17th was representative of the one used in the final round in 1913, when local amateur Francis Ouimet made a critical birdie on his way to victory.
And the 18th was in a similar position to that used in the final round in 1988, when Curtis Strange saved par from a greenside bunker to force a play-off against Nick Faldo.
Strange won the 18-hole play-off by four shots and successfully defended his title the following year.