The five-time major winner shot a six-over-par 76 in Friday's second round at Cherry Hills, leaving him tied for 63rd in the 69-man field and some 14 shots adrift of leader Sergio Garcia.
Mickelson required a finish of fourth or higher to make the Tour Championship next weekend, and with that possibility becoming increasingly unlikely, the 44-year-old has opted to end his participation in Colorado.
The American will now focus his attentions on the Ryder Cup, which begins at Gleneagles on September 23.
"My primary goal is to rest and prepare for the Ryder Cup," Mickelson said in a statement released on the PGA Tour's official website.
"Without a chance to contend at the Tour Championship, the most important thing for me now is to prepare for the Ryder Cup."
Mickelson came into the FedExCup play-offs as just one of three men along with Hunter Mahan and Steve Stricker to have featured in the Tour Championship every year since its inception.
Only Mahan will be able to claim such a record next season as Stricker did not feature in this year's play-offs.
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