Rose, a second-round co-leader, finished 54 holes at 13-under 200 and is four strokes clear of Australian John Senden, who had a one-under 70 on Saturday.
This is the third PGA Tour Playoff event for the FedExCup and this event was reserved for the top 70 on the points list. The top 30 after Sunday's final round move on to the Tour Championship next week, and after that, someone walks off $10 million richer and with the FedExCup.
Rose began the week 34th in the Playoff points race, but, if he were to hold on for his third PGA Tour victory, he'd leap into third.
"I'm aware that if I win I go to third," said Rose. "We've heard about being in the all important top five going into Atlanta, so it would certainly be a huge win at the right time."
The top five on the points list heading into next week control their own destiny. If one of them wins the Tour Championship, he wins the FedExCup, but the Playoff race isn't the only one going on this week.
This is the final event to earn one of the 10 automatic spots on either the U.S. or International Presidents Cup teams.
Geoff Ogilvy and Bill Haas are bubble players for their respective teams. Ogilvy, who is 10th on the International list, shot a three-under 68, while Haas, currently just on the outside looking in at the American top 10, carded a 69. The pair is knotted in third at eight-under 205.
Webb Simpson leads the Playoffs points race based on his win at the Deutsche Bank Championship two weeks ago and on Saturday, he struggled to a two-over 73. Simpson is alone in fifth at minus-seven.
PGA Champion Keegan Bradley, who needs a win to make the American Presidents Cup team on points, managed a one-under 70 on Saturday at Cog Hill and is sixth at six-under 207.
They'll all be facing the uphill battle of catching Rose with a four-shot lead.
After pars at his first three holes, Rose broke into red figures with an 11- foot birdie putt at the fourth. He made it two in a row with a 25-footer at the fifth.
Second-round co-leader Mark Wilson bogeyed three and seven and Rose found himself four strokes clear of everyone.
The Englishman cruised with six straight pars around the turn, but ran into a spot of bother at the par-three 12th. Rose's tee ball landed in a greenside bunker and he blasted his second through the green to the fringe. Rose knocked his third to seven feet and holed that clutch putt just to save bogey.
Wilson was stumbling so Rose didn't lose any ground. In fact, he rebounded very quickly thanks to a wonderful approach to five feet to set up birdie at the 13th.
Rose was 13-under par and stayed at that number, although the closest he came to losing a stroke was at the last. He drove into a fairway bunker, then hit his second into the right rough. Rose pitched his third just inside nine feet, then drained the par putt to keep his four-shot lead with one round to go.
"Four-shot lead isn't really a big enough lead to go out and try and waste holes," said Rose. "You know that any guy out here is good enough to make a run at you, so you never know what to expect, you've just got to go out and give it 100 percent."
Rose's only two victories on tour came during a good run last year. He captured the Memorial and AT&T Classic and this is the eighth time he's held at least a piece of the 54-hole lead on tour. The win last summer at Aronimink was the only time he made it to the winner's circle.
Wilson shot a six-over 77 on Saturday and fell into a tie for seventh with world No. 1 Luke Donald (67), Sergio Garcia (67), Brandt Jobe (69) and last year's FedExCup champion Jim Furyk (70). The group finished at five-under 208.
NOTES: Tee times were moved up on Saturday to accommodate NBC's coverage of Notre Dame football...David Toms and Brandt Snedeker are 10th and 11th on the U.S. Presidents Cup points list and will be paired together on Sunday...Phil Mickelson shot an even-par 71 and is tied for 42nd at three-over par...Defending champion Dustin Johnson, who is second in Playoff points after this win at The Barclays, posted a two-over 73 and is 63rd at plus-eight.