The Northern Irish world number six, just four days after winning the European Tour's flagship BMW PGA Championship at Wentworth, recorded two eagles on his back nine to seize control of the elite US PGA Tour event hosted by Jack Nicklaus.
Though McIlroy was troubled by a sore left knee from his seventh hole of the day, he surged up the leaderboard with a brilliant homeward nine of 31 that included a double-bogey at the 14th.
"I obviously played really well from tee to green," McIlroy told Golf Channel after totalling only 22 putts and ending the first round three ahead of Americans Bubba Watson and Chris Kirk, and Englishman Paul Casey at Muirfield Village Golf Club.
"I holed a lot of putts as well, two really good up-and-downs at the last two holes. It could have been even better apart from that double-bogey on 14, but I am really happy."
McIlroy, whose victory last week came just days after he broke up with his tennis-playing fiancee Caroline Wozniacki, drained a 28-foot putt to eagle the par-five 11th, then sank a 15-footer for eagle at the par-five 15th.
His only blemish of the day came at the par-four 14th where he pulled his wedge approach into a horrible lie in a greenside bunker.
Asked what was wrong with his left knee, McIlroy replied: "Honestly I don't know. I felt it on my second shot on (hole) seven today. I think my foot might have just got stuck in the ground a little bit and torqued my knee.
"It was painful right after I hit shots and then I sort of walked it off for the next one and it was okay, and then it would be painful again. I guess I put it out of my mind when I was over the golf shots.
"I'm going to go and get some treatment on it now and have a physio look at it. Hopefully it will be all right for tomorrow. This is a new injury. I haven't felt this before."
Masters champion Watson, the world number five who is among seven players in the top 10 competing this week at Muirfield Village, was delighted with his opening round on a rain-softened course with barely a breath of wind.
"They are generous fairways around here so I can keep the ball somewhat in play," the American left-hander said after ending his round with four birdies in the last five holes.
"If I hit my driver well, it's shorter irons into some of the par-fours and the par-fives are reachable if you hit decent tee shots. And today I played the par-threes pretty good.
"I am making a few putts here and there and birdied the last few holes. Making those key putts coming down the stretch obviously makes a good score."
Casey, whose only victory on the US Tour came at the 2009 Houston Open, was also in an upbeat mood after his first competitive round at Muirfield Village since 2009.
"That was a joy today," Casey said. "I thought the golf course (was) in impeccable shape. It's beautifully set up. I'm very happy with a six under."
Australian Adam Scott, who clinched the Crowne Plaza Invitational on Sunday and is making his second consecutive appearance on the US Tour since replacing Tiger Woods as world number one, opened with a 69 playing in the company of McIlroy.
US Open champion Justin Rose of England, who won the 2010 Memorial Tournament, returned a 73 while American world number four Matt Kuchar, launched his title defence at Muirfield Village with a 74 that included two double-bogeys.
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- Bubba Watson
- Muirfield Village Golf Club