The Masters champion shot a 66 with six birdies in all and bogeys on the 11th and 15th holes.
He was five strokes behind the day one leader, America’s Keith Mitchell who finished on Thursday at nine under.
Mitchell took full advantage of the different surroundings, setting a new course record with a nine-under-par 61 as only eight of the 72-strong field failed to break par.
After opening with five straight pars, the American birdied nine of the remaining 13 holes to lead by one from Denny McCarthy.
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World No 2 McIlroy played alongside Shane Lowry at the Zurich Classic of New Orleans and is now competing as the defending champion at the Truist Championship, previously called the Wells Fargo Championship, ahead of next week’s PGA Championship.
“I was a little rusty out there, just hadn’t played in a week and I hadn’t really done a ton of practice,” said McIlroy.
“I drove the ball pretty well. I certainly can tidy a few things up, but overall a decent day.”
Collin Morikawa, Rickie Fowler, Sepp Straka and Akshay Bhatia were a shot further back with Lowry and US Ryder Cup captain Keegan Bradley among a group on six-under-par.
The Truist Championship is taking place at the Philadelphia Cricket Club in Pennsylvania rather than the Quail Hollow Club, where the PGA Championship will be held next week.
Lowry is tied for seventh after a bogey-free opening round of 64.
McIlroy became only the sixth player ever to complete a career Grand Slam with his dramatic victory in The Masters last month. He is looking to build towards a sixth major victory at the PGA Championship with another title win at this Signature Event this week.
“I don’t want to diminish this tournament and this championship, but to me, with everything that’s happened over the past couple of weeks, this was always going to be a great prep week for me to see where my game was and sort of refine a few things,” McIlroy said.
“I still want to play well, and I still want to have a chance to win the tournament, but I’ll have a much better gauge of where my game is going into next week after these four days than I would have had if I hadn’t had played or if I just spent the week at home practising. It’s an important week for me.
“Hopefully in two weeks’ time you’re talking about me being a six-time major champion instead of a five-time major champion.”