"I'm not in a great place mentally," McIlroy told reporters in the car park after making a swift departure.
"I can't really say much, guys. I'm just in a bad place mentally.''
The US PGA Tour's official twitter feed then claimed that McIlroy withdrew "with severe wisdom tooth pain affecting concentration."
Later McIlroy released a statement confirming the issue with his teeth.
"It began bothering me again last night, so I relieved it with Advil," he said.
"It was very painful again this morning, and I was simply unable to concentrate. It was really bothering me and had begun to affect my playing partners."
It is unclear why McIlroy did not mention his toothache when first confronted by reporters. He was also photographed eating a sandwich on the hole where he eventually withdrew.
Earlier this week his girlfriend Caroline Wozniacki was knocked out of a tournament in the first round by a qualifier. The two defeats for the young stars has fuelled speculation across the media that sport's highest-profile young couple may have gone their separate ways.
The US PGA Tour said it was the first time the Northern Irishman had withdrawn from a tournament.
World number one McIlroy had fired an even-par 70 in the first round at the PGA National Resort and Spa in Palm Beach, Florida.
"If I had been playing well or playing the way I know I can there is something in the mid-sixties out there," said the 23-year-old Northern Irishman after that round.
However a slow start to the second round saw the defending champion drop out after a triple bogey, a double bogey and two pars on Friday morning.
After hitting his approach shot into the water on the 18th, his ninth hole of the day, McIlroy walked off the course with his coach and caddie.
McIlroy would almost certainly have missed the cut but his decision to quit was criticised by playing partner Ernie Els who said: "I'm a great fan of Rory's but I don't think that was the right thing to do."
Els later said McIlroy deserved credit for playing through pain while denying that the 23-year-old Northern Irishman's discomfort had been affecting his partners.
"All credit to him but no. I've played like that before. It's embarrassing. You don't want to be out there while you feel like, get me out here," said the South African, the current Open champion.
Beginning play on the 10th hole, McIlroy struggled from the start. He nearly hit his approach to the 11th hole into the water before chipping through the green and making a double bogey.
Two holes later, he made another bogey after driving to the right and being forced to lay up. He missed a six-footer to save par.
On the par-four 16th, McIlroy hit his tee shot into the water, took a drop, then hit another into the water before carding a seven. He then three-putted to go seven over after eight.
"I came here with every intention of defending my Honda Classic title. Even though my results haven't revealed it, I really felt like I was rounding a corner," added McIlroy.
"This is one of my favourite tournaments of the year and I regret having to make the decision to withdraw, but it was one I had to make."
This season he is adjusting to Nike clubs after switching from Titleist, having signed a 10-year contract worth a reported £150 million.
Nick Faldo said at the time that the change of manufacturer was “dangerous”, adding that he was "doing it for the money".
Twice Major champion Sandy Lyle also said he hoped McIlroy's decision to switch golf clubs would not result in the same sort of "kamikaze dive" in form that David Duval suffered when he made a similar move.
McIlroy missed the cut at the recent Abu Dhabi HSBC Championship by four shots and also lost his first-round match at the WGC-Accenture Match Play Championship to Shane Lowry of Ireland.
Prior the this week's tournament, McIlroy said he was still in "an adjustment period" but stressed he was more concerned with his swing than the feel of new clubs.