The Scot entered day three at The Celtic Manor Resort four shots off the lead and while he turned in 33, he and the rest of the field were simply trying to keep pace with a flying Thomas Pieters.
But the big-hitting Belgian stumbled down the stretch while Syme came home in 30 to get to 15 under and lead the way.
England’s Sam Horsfield is looking for his second win of the UK Swing and he was Syme’s nearest challenger after a 68, one shot clear of Swede Sebastian Soderberg.
Soderberg was blemish free in a 65 that left him a shot ahead of Belgian Thomas Detry, England’s Andrew Johnston and Pole Adrian Meronk.
Pieters was then at 11 under alongside England’s Callum Shinkwin.
Having graduated from both the Qualifying School and the European Challenge Tour in his career, Syme claimed a victory at last season’s Turkish Airlines Challenge.
After improving his result every week so far on the UK Swing, he takes a lead into the final round of a European Tour event for the first time and will be looking for a first victory after finishing second at the 2018 Shot Clock Masters.
“I felt like I played well in Austria, the first event back, but then a bit slow after that to start the UK Swing,” he said. “I’m finding a bit of form. I made the cut at the Hero Open and then gradually a little bit better last week.
“I found something a little bit in my swing and I’m just rolling with that really.
“It’s a new experience for me – I’ve obviously had a second place before – but it’s the first time with a chance to win. I’m just going to take it as it comes.
It’s the first time with a chance to win. I’m just going to take it as it comes
“It’s obviously going to be great. It’s a great opportunity and that’s all you can hope for at the start of any week.”
Pieters took advantage of the par five second to join Horsfield at the summit and approaches to inside four feet at the fourth and fifth moved the big hitting Belgian two clear.
He missed the green and failed to get up and down on the seventh and Syme was creeping up the leaderboard as he holed from ten feet on the 11th to make it three out of three on the par fives, adding to a gain on the sixth.
Another birdie on the 12th then moved him into a share of the lead but Pieters found the fringe with his second on the par five ninth and holed from 25 feet to jump clear, with Horsfield breaking a run of eight pars with a two putt birdie.
Pieters dropped a shot on the tenth and Syme rejoined the lead with a big left to righter on the 14th but Pieters holed a monster on the 11th for another eagle and a two shot lead.
Syme holed from seven feet on the 15th and 12 feet on the penultimate hole to once again find himself in a share, while Horsfield took another step forward with an eight foot putt on the 14th.
Pieters then found an unplayable lie off the tee at the 15th and put his second tee shot into the penalty area as he recorded a triple bogey and followed it with a dropped shot on the next.
Horsfield then added another birdie on the 16th to move into solo second.
Soderberg picked up shots on the seventh and 11th and then made a hat-trick of gains from the 13th before adding a two putt birdie on the par five last.
Detry and Johnston both carded rounds of 68, while Meronk – looking to become the first Polish winner in European Tour history – carded a European Tour career low 64.
Pieters came home in 38 in his round of 70, with Shinkwin carding a 69.
Australian duo Jake McLeod and Jason Scrivener, Dutchman Wil Besseling, Northern Ireland’s Cormac Sharvin and Scot Marc Warren were at ten under.
European Tour Release, Aug 16, 2020
