The American world number 12 pulled out of the elite event hosted by Jack Nicklaus at Muirfield Village Golf Club after covering his back nine in six-over 42.
"I think mentally I'm a little bit fatigued," Mickelson said. "The course here is in such great shape. It's a beautiful way to get ready for the U.S. Open.
"But I'm hitting it so poorly ... I have to look at what's best for me to play in the U.S. Open, and I'm going to take the next few days to kind of rest up."
The U.S. Open, the second of the year's four Majors, will be played from June 14-17 at San Francisco's Olympic Club.
"Certainly I'm disappointed with how I played today, but I've got to be more big picture oriented and think about the (U.S.) Open and what's best to get my best golf out there," Mickelson said. "I need the next few days to rest up a bit."
Mickelson said his fatigue built up after he took his wife Amy to Europe last week to celebrate her 40th birthday, having previously played three consecutive events on the U.S. PGA Tour.
"We went to Italy and Paris," the four-times Major champion added. "I came back and had a Tuesday outing in Long Island, the pro-am. Mentally I'm a little bit fatigued."
Mickelson played in a high-profile grouping on Thursday with Masters champion Bubba Watson and fast-rising American talent Rickie Fowler.
Hardly surprisingly, they attracted a huge gallery with several fans repeatedly taking pictures of the players with their cell phones, which are now permitted in specific areas at U.S. PGA Tour events.
Asked whether such distractions had been a factor in his poor form at Muirfield Village, Mickelson replied: "I think it was more that mentally I wasn't able to focus as well from the last month more than anything."
Mickelson, a 40-times champion on the U.S. PGA Tour, could not recall a previous occasion when he had to withdraw from a tournament without suffering an injury.
"It very well could be," the American lefthander said. "I feel like it's the responsibility of a player to see through your commitment (to play) and finish the tournament and so forth.
"I'm kind of overruling that just a touch because I'm trying to think big picture on what's the best way for me to get ready for the Open."