The British Open champion, in pursuit of a third consecutive victory on the PGA Tour, fired a four-under-par 67 on a wet, ultra-long Valhalla layout where play was suspended for 45 minutes earlier in the day due to water-logged conditions.
McIlroy, the pre-tournament favorite heading into the year's final major, holed an uphill 30-foot putt from just off the green to eagle the par-five 18th and also recorded four birdies and two bogeys to post a nine-under total of 133.
Four-times winner Tiger Woods, however, ended a miserable week prematurely when he missed the cut at a major for only the fourth time as a professional, looking tournament rusty in both rounds as he carded successive 74s.
McIlroy squandered a golden opportunity to add another eagle at the par-five seventh, where he hit a brilliant second shot from 243 yards to eight feet before missing the putt, but signed off with a birdie at the ninth where he drained a 16-footer.
"I played well for the most part," world number one McIlroy told reporters after moving a step closer to winning the fourth major title of his career. "Scored really well. Some key up-and-downs to keep the momentum going in the round.
"I'm very pleased. I'm in a great position going into the weekend in another major championship. Can't ask for much more. I'm confident, and I'm just on a good run.
"You've seen before when I got on good runs like this, I can sort of keep it going for a little while," said the Northern Irishman, who won last month's British Open before clinching the WGC-Bridgestone Invitational last Sunday in his next start.
McIlroy ended his round one ahead of Australian Jason Day, who fired a best-of-the-day 65, and veteran American Jim Furyk (68). Americans Rickie Fowler (66) and Ryan Palmer (70), and Finland's Mikko Ilonen (68) were a further stroke back.
Five-times major winner Phil Mickelson (67) was next best on a high-quality leaderboard, level at six under with Austrian Bernd Wiesberger (68).
England's former world number one Lee Westwood (72), fourth-ranked Swede Henrik Stenson (71) and American Steve Stricker (68) were among a group of seven players knotted at five under.
McIlroy, however, commanded the spotlight as he lived up to his pre-tournament billing with another consummate display in the more difficult playing conditions of the morning.
Initially struggling for accuracy off the tee, he dropped a shot at the par-four 12th where he found a bunker with his approach, but swiftly responded by sinking a 12-footer at the 13th and a 16-footer at the 15th to get to six under.
Though the 25-year-old Northern Irishman squandered another birdie chance at the 16th, where he missed an eight-foot putt, he reached the turn in sizzling style with his eagle on 18.
McIlroy dropped another shot at the par-four second, where his tee shot ended up in the rough and his second in a bunker, but maintained his grip on the tournament with two birdies in his last three holes.
Day, among the late starters on Friday, surged into contention for his first major title with birdies on his last two holes, having earlier eagled the par-five seventh.
"I think we got a little lucky on the draw, teeing off in the afternoon," said the 26-year-old from Queensland. "We didn't get as much rain. I played great.
"A little disappointed that I had one bogey on the back nine but I came home strong with birdies on 17 and 18."
The cut fell at one-over par, leaving Woods well out of the picture after he finished at six over.
Tournament rusty after having surgery in late March to treat a pinched nerve in his back, Woods struggled to an opening 74 on Thursday and he tumbled further backwards by dropping four shots in his first seven holes on Friday.
Also missing the cut were U.S. Open champion Martin Kaymer of Germany and triple major winner Padraig Harrington of Ireland.
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