In dazzling sunshine with light breezes coming in off the ocean at Kiawah Island Golf Resort, the Northern Irishman fired a five-under-par 67 to hold the clubhouse lead with long-hitting American Gary Woodland in the season's final major.
Defending champion Keegan Bradley, fellow American John Daly and 2006 U.S. Open winner Geoff Ogilvy of Australia opened with 68s while world number two Tiger Woods was among a group of four players knotted on 69.
McIlroy, who won last year's U.S. Open by a staggering eight shots, sank a 12-footer to birdie his opening hole, the 10th, and picked up further shots at the 14th, 16th, second and sixth to rocket into contention.
"It's a great way to start the tournament," McIlroy told reporters after a bogey-free display in hot and humid conditions on the ultra-long, 7,676-yard Ocean Course.
"Hitting balls on the range this morning, there was completely no wind. It was flat calm and I really thought that I had to take advantage of the conditions.
"I was three under through seven (holes) and just took it on from there, so very happy with the round. It's a great score to build on."
Woodland, who sank a long-range putt from just off the green to eagle the par-five 11th, took advantage of his booming power off the tee to join McIlroy at five under.
"I drove the ball great today," the 28-year-old said after also recording four birdies and a lone bogey in his opening round on the longest layout to stage a major championship.
"Out here there's a lot of holes where I can take advantage of the driver and hit my irons into all the par-fives, which is a huge advantage. Me driving the ball in the fairway I gave myself a lot of chances and made a couple putts coming in."
Most eyes, though, were on four-times champion Woods who teed off at the 10th in pursuit of his 15th major title but his first since the 2008 U.S. Open.
Following an early birdie at the 12th, he bogeyed the 13th, after finding bunkers off the tee and also with his third shot, and the tricky par-three 14th, where he missed the elevated green to the left off the tee.
However, Woods immediately recovered by sinking a 15-foot birdie putt at the 15th, sparking a cry of "beautiful" from a fan, before rolling in a 25-footer on the 18th green to prompt huge roars from the crowd crammed into the grandstands.
Woods also birdied the first and second, stumbled with a bogey at the fourth, then picked up one more shot at the par-three eighth to finish three strokes off the early lead.
"I'm pleased," said Woods. "Anything in the 60s is a good score. I putted well, I just have to clean up a few things."
British world number one Luke Donald, Masters champion Bubba Watson and South African Ernie Els, winner of last month's British Open, were among the late starters at Kiawah Island.
Weather forecasts predicted a mix of sunny and cloudy conditions, along with heat and humidity, for the rest of Thursday with a chance of thunderstorms in the late afternoon.
