Rose finished at 13-under-par 271 for his third PGA Tour title.
The Englishman had won just one of the previous seven times in which he held at least at share of the 54-hole lead. He headed to the 17th hole with just a one-stroke lead.
Rose chipped in for birdie on No. 17 to seal the victory.
"I've had my ups and my downs, and the learning curve is steep sometimes," Rose said in a televised interview. "You know, what doesn't kill you makes you stronger, and if you can put it into perspective, that's when the game isn't a big deal."
John Senden posted a two-under 69 at Cog Hill to take second at minus-11.
Geoff Ogilvy also closed with a 69 to grab third place at 10-under-par 274. With that finish, Ogilvy clinched both the final spot on the International team at the Presidents Cup, and also a spot in the field next week at the Tour Championship.
"I was looking at it as a win-win. If I did well enough to get into the Tour Championship, I get another week to play; if I don't, I get an extra week to spend with my family next week," Ogilvy said on TV.
"I'm glad I played well. I holed some putts the first three days, and I hit the ball really well today on a hard day."
Ogilvy wasn't the only one battling for spots in those two events. Both Presidents Cup teams remained the same as the top 10 on the points list for both squads went unchanged.
The top 30 on the FedEx Cup points list will head to East Lake next week for the Tour Championship. Bo Van Pelt tied for 56th on Sunday and fell from 22nd to 30th in the FedEx Cup race, earning the final spot at East Lake.
Rose, Senden and Ogilvy all moved into the top 30 and will have a shot at winning the FedEx Cup next week.
Among the unlucky ones were Martin Laird and 2010 FedEx Cup champion Jim Furyk. Laird, who started the week 31st on the points list, birdied three of the last five holes to shoot two-over 73 that left him tied for 12th at minus- two, but also at No. 31 on the points list.
Furyk struggled to a five-over 76 to end 36th on the points list. He will not be in the field to defend his title at the Tour Championship and he won't repeat as FedEx Cup champion.
As all that was playing out, Rose and Senden were battling to win the tournament. Rose tripped to a bogey on the second, but rebounded with birdies on six and seven, both from inside 10 feet, to move to 14-under.
Rose was five clear at that point, but trouble loomed. There was a two-stroke swing on No. 9 as Rose made a mess of the par-five for a bogey, while Senden converted a birdie try.
Senden made it two in a row with a birdie on the 10th to get within two of Rose's lead.
Rose drove under a bush on the par-five 15th and he had to take an unplayable lie penalty, leading to another bogey and cutting his margin down to one stroke.
The Englishman came up short with his second shot to the par-four 17th, but hit a perfect chip shot that rolled into the hole for birdie. He was two clear heading to the last and finished there with a two-putt par to win the title.
"I nearly took the chicken stick out and putted it. Then I said to myself, 'Come on, this is a really makable chip shot,'" said Rose on TV. "I just had to commit to it and do what you've got to do to win a golf tournament."
Senden had a steady round. Other than his birdies on nine and 10, the Australian carded 16 pars to post his fourth career runner-up finish.
NOTES: Rose earned $1.44 million for the win. He said afterward that he thinks it was the first time he's even gone wire-to-wire to win a golf tournament...Despite his tie for sixth, Villegas did not qualify to play at East Lake next week.