The 25-year-old McIlroy, already a two-time major champion and the fan favorite here because of his promise and his United Kingdom address, shot a six-under-par 66 to lead by one.
In second place alone was Italy's Matteo Manassero, four years younger than McIlroy and already a multimillionaire on the European tour. He started with a birdie, finished with a birdie and stayed in red numbers all day for his 67.
Two other Italians, brothers Edoardo and Francesco Molinari, were among seven players at four under. That group also included Jim Furyk, Sergio Garcia and world No. 1 Adam Scott, as well as Florida State's Brooks Koepka, who finished fourth at this year's U.S. Open.
Tiger Woods, barely three months from serious back surgery, had a great start, all things considered, with a three-under 69.
He started with two bogeys, then rallied with six birdies and said afterward, "I knew I could do it. That's why I was telling you guys it was so important for me to play [the recent tournament] at Congressional. The fact that I was able to recover every day, and the fact that I was more explosive the more days I played…. I'm only going to get stronger from this point."
McIlroy, who has a tendency to start fast and follow with a horrible round Friday — his "freaky Fridays" — took the lead for good on the par-five 16th hole, where he hit his driver 372 yards and made a short birdie putt for six under.
On the next two holes, the par-four 17th and par-five 18th, he drove the ball into rough and had to settle for pars.
Still, he was pleased.
"Any time you shoot 66 at the Open Championship," he said, "you are going to be pleased. We had perfect scoring conditions out there."
The usual severe weather that distinguishes the British from other majors didn't materialize Thursday. Temperatures were in the mid-70s and winds were light. Forecasts for Friday were for that to change somewhat, maybe even radically, with higher winds and possible heavy rain on the way.
Phil Mickelson, the defending champion, hit his second shot out of bounds on the 18th, had to retrace his steps and hit again, then hit that shot into the high rough next to the green. But he got up and down for a bogey and stayed within striking distance with a two-over 74.
Furyk played in a sort-of senior citizen threesome. He is 44, a former U.S. Open champion. He played with Darren Clarke, 45, the 2011 British Open champion, and with Tom Watson, 64, a five-time British Champion.
"…It was a pretty cool thing with Tom," Furyk said. "We had a couple of standing ovations on tee boxes, even early this morning.…Seeing the reception he got from the crowd was pretty special."
Clarke, who has lost nearly 60 pounds, shot par and Watson shot one-over.
Ernie Els, a two-time British champion, had a bad day. On the first hole, his drive hit a fan and drew blood and then, possibly still shaken by that, three-putted from two feet. His first little two-footer slid past, then he tried to casually backhand his next put into the hole and that missed, too.
Els finished with 42 on the front and 79 for the day and has a long road to even make the cut.
Bryden Macpherson also had a rough day. The 23-year-old former British Amateur champion from Australia, by way of the University of Georgia, shot 41 on the front and opened his back nine with 7-6-8-4-7. He shot 90.