McIlroy eagled the par-five 16th and added a birdie for good measure at the par-three 17th for a second-round seven-under-par 65 on another benign day at TPC Sawgrass. The Northern Irishman caught Fleetwood (67) at 12-under 132, well clear of Americans Jim Furyk and Brian Harman, Mexican Abraham Ancer and Briton Ian Poulter in a share of third.
Tiger Woods was nine strokes adrift after a 71 that included only one blemish on his card. It was a big one, however, a quadruple-bogey at the island-green 17th, where he hit two balls into the water.
McIlroy has been in tremendous form this year, doing everything but win with no finish worse than sixth in his five starts. But his Ryder Cup team mate Fleetwood is unlikely to be intimidated when they play together in the third round on Saturday.
"It was a bit more up and down today but absolutely felt really good out there," said the Englishman. "Drove it really well, a couple of mishaps but that's always going to happen. Really happy with 67. Will take that and run away."
Not that it is yet a two-horse race, not with a group of thoroughbreds lurking and conditions forecast to become much tougher over the weekend as a cool northerly breeze sweeps through Florida. Third-placed Furyk turned back the clock 64, his best-ever score on a course that is not his favourite, even though he lives locally.
"It's not that I dislike the course. It's just I have a lot more on tour I'm more comfortable on," said the 48-year-old. "We're all selfish. My track record is not great. As I've grown on tour, I've got a little more comfortable on this course.
"No bones about it, you're not going to fudge your way around this course for very long." Furyk has won 17 times on the PGA Tour, including the 2003 U.S. Open. His best finish at the Players is a second place in 2014.
He did not get an automatic exemption into the event this year, but sneaked in when some other players withdrew injured. "I was the last guy in the field so it was a nice opportunity for me, one I did not expect," he said.
"It was definitely a sigh of relief Sunday night finding out I was in." Eighty players made the cut, which fell at one-under.
Big names heading home early included Phil Mickelson and Jordan Spieth. (Reporting by Andrew Both in Cary, North Carolina; Editing by Toby Davis)