The Holywood man blazed a trail to the top of the leaderboard as he took advantage of the warm conditions and mild wind at a receptive Hoylake links on Thursday.
McIlroy, who began as one of the favourites, lived up to his billing with some fantastic approach play giving him plenty of opportunities for low-scoring.
The 25-year-old former world number one carded a birdie on the second hole before picking up a further two shots at five and six to reach the turn at three under.
More birdies were to follow at two of the par fives - the 10th and 16th - and the 447-yard 12th, as McIlroy edged one stroke ahead of Italian Matteo Manassero.
He finished with pars on the final two holes to complete his round without any dropped shots, putting him out in front on six under and very much in contention for a first Open title.
However all eyes will be on how McIlroy follows up on Friday as he seeks to cure a second-day syndrome which has seen his PGA Tour-leading first-round scoring average of just under 68 consumed by a second-round average almost five shots worse.
It's another great start and I’m looking forward to getting back out there tomorrow.
The Co Down golfer said he's looking forward to following up a strong round but may well find himself having to cope with a change in the weather as an afternoon starter.
McIlroy said: "Any time you shoot 66 at the Open Championship, you're going to be pleased.
"We had perfect scoring conditions out there this morning. There wasn't much wind early on and there were plenty of opportunities to make birdies and I was able to take a few of them.
"Whenever I go out and play on Thursdays there's not really many expectations. You're going out there and you're trying to find a rhythm and you're just trying to play your way into the round.
"When you go back out on Friday after a good score you know what you can do, so you're going out with some expectations compared to Thursday. I think I've just got to approach it like that, and start off trying to hit solid shots the first few holes and play my way into the round, just like I did today."
Shane Lowry is also in contention after he came in with a four under 68.
Meanwhile a rusty Tiger Woods recovered well after dropping two shots on the first two holes as he put in a brilliant back nine, in what is only his second event since a back operation in March.
The 14-time major winner closed with five birdies and one bogey for a -3 round of 69.
Woods said: "I'm getting stronger, I'm getting faster, I'm getting more explosive. The ball is starting to travel again and those are all positive things."
Northern Ireland golfers Graeme McDowell and Darren Clark were on two under and par respectively, while Michael Hoey was three over.