Manassero shot a nine -under 63 to take a three-stroke lead after the third round at Wentworth, England, on Saturday.
Victory would cap a career revival for Manassero, who as a teenager was widely expected to become a golfing superstar.
His game went into freefall, dropping the Italian onto the third-tier Alps Tour and to a world ranking of 1,705.
Back on the European tour this year, he won in South Africa in March and is in sight of a victory over a stacked field at the tour's flagship event.
"Thinking of the difficult years, to be standing here right now in the lead — it feels amazing," Manassero said.
"My perspective has changed. I'm going to go out and enjoy tomorrow."
Manassero, now ranked No. 101, pumped his fist after curling in a 12-foot putt at the last to seal a birdie-birdie-birdie finish and a back nine of 31 on the storied West Course that was drenched in heavy rain for much of the round.
He made seven birdies and an eagle three at the fourth and was 18 under for the tournament.
"I have to be honest, one of the best rounds I've ever played," Manassero said.
Rory McIlroy shot 66 after getting up and down for par at No. 18 after hitting into water off his second shot.
The No. 3-ranked Northern Irishman, who won the event in 2014, was tied for second place with American 2021 champion Billy Horschel, whose round of 65 included a run of seven straight birdies — featuring holed putts totalling 130 feet — from No. 8.
Overnight leader Matthew Baldwin, who is ranked No. 363 and was dropping off packages for Amazon two years ago, shot 71 and was alone in fourth place.
McIlroy, who also has two runner-up finishes at Wentworth, came from seven shots back at the start of the final round to win a decade ago and said catching Manassero might be just as difficult on Sunday.
"It's good to see him back playing the golf that he is and where he's supposed to be," McIlroy said of Manassero, "so it's going to be an exciting day.
"But if I get off to a fast start, it's game on."
8°C