The 2010 champion fired a six-under 66 to catapult to 15-under-201 for the tournament. That put the 2013 U.S. Open champion three clear of Italian Francesco Molinari (69) and Swedish overnight leader David Lingmerth (72) who shared second at 12-under.
American veteran Jim Furyk (70), also a former U.S. Open and Memorial winner, sits fourth at 11-under.
Tiger Woods, a 14-time major champion, carded the worst round of his professional career, a disastrous 13-over 85, to balloon to 12-over and last place.
“Obviously a lot has been going right," said Rose. "I guess I played a good, solid, patient round of golf that ended up turning into a great round of golf.
“I made my birdies when I had a chance and I limited the mistakes. Kind of surprised to play my way into a three‑shot lead. I was looking just to keep pace, but it's a fantastic position going into Sunday.”
Rose kick-started his American career with a victory here in 2010 and the 34-year-old made no bones about the initial win being critical.
“If you look at my career, to be honest with you, you could say it's gone from strength to strength since getting the monkey off my back and winning here,” he added.
“As time ticks on, it becomes harder and harder so to finally do it and do it at a place like this and a tournament of this stature was fantastic."
Rose opened strong with four birdies in his first seven holes and while he bogeyed the ninth, three further birdies on the back side set up his comfortable buffer.
Woods’ round marked just the third time in his professional career he has failed to break 80. He had an 81 in the 2002 British Open and an 82 earlier this year at the Phoenix Open.
The former world number one, who has slumped to 172nd in the global rankings, found water hazards four times. He struggled to find fairways, getting just seven of 14.
Just a day after making a clutch par putt to make the cut on the number, the five-time event champion managed just one birdie while carding six bogeys, two double bogeys and the quadruple bogey.
(Editing by Gene Cherry)
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