Since winning the last of his four majors in the 2014 US PGA, McIlroy is a combined 35 over par in the first round of golf's four biggest tournaments, his latest effort being a one-over-par 73 in April's Masters.
But, perhaps inspired by being paired with Tiger Woods and Jordan Spieth - who is chasing the career grand slam in Tulsa - it was a different story at Southern Hills, where Woods won the 13th of his 15 majors in 2007.
Starting on the back nine, McIlroy parred the 10th and 11th before hitting a superb approach to two feet on the 12th to set up a tap-in birdie.
The par-five 13th measures 628 yards but McIlroy was able to reach a greenside bunker in two and get up and down for birdie before holing from 25 feet on the 14th and 10 feet on the next to make it four in a row.
Pars on the 16th, 17th and 18th took McIlroy to the turn in 31 and a shot ahead of American Davis Riley, with Justin Rose part of the group a stroke further back on two under.
Woods had made the ideal start with a close-range birdie on the 10th and also picked up a shot on the 14th - after using one of several waits on the tee to tuck into a large sandwich - before dropping his first shot of the day on the 15th following a badly mishit tee shot.
Another bogey on the ninth, caused by a pulled approach into a bunker, dropped Woods back to level par, with Spieth two over following three bogeys in the space of four holes.
The marquee group had taken two hours and 40 minutes to complete their first nine holes, with the course layout at Southern Hills causing several bottlenecks.
The second green, third tee, fifth green, sixth tee and seventh tee are all within close proximity of each other, while the first and 10th holes head in different directions from the same small teeing ground.
McIlroy missed from eight feet for birdie on the fourth but smashed a drive and long iron into a greenside bunker on the 665-yard fifth and got up and down to improve to six under.
With Southern Hills a par-70, McIlroy needed to complete the last four holes in two under to equal the lowest score in any men's major, Branden Grace carding an eight-under-par 62 in the 2017 Open at Royal Birkdale.
McIlroy's round was in danger of tailing off when he bogeyed the sixth and eighth - both long par threes - but he finished in style with a birdie on the ninth to complete an opening 65.
"It was a great start to the tournament," McIlroy said. "I have been playing well coming in here and took a lot from that last round (64) at Augusta.
"I feel like this course lets you be aggressive if you want to be so I hit a lot of drivers to take advantage of my length and hit a lot of good iron shots.
"I did pretty much everything you need to do out there and I'm going to have to keep doing the same the next three days. I'm not getting ahead of myself."
Pádraig Harrington, meanwhile, ended his opening round with a +7 round of 77.