Perry shot a 6-under 66 on Sunday to finish at 19-under 269, one shot better than Woody Austin, who blew the tournament and $900,000 by bogeying the last two holes, and Bubba Watson, who missed a 12-footer on the final green.
Vijay Singh has three victories at Warwick Hills. Tiger Woods, Julius Boros, Tony Lema and now Perry have won twice.
Perry, who won in 2001 at Warwick Hills, has 11 victories on the PGA TOUR, including the Memorial earlier this month. After winning the Memorial, he stuck with his plan to not enter a U.S. Open qualifier.
Austin and Watson shot 68s. Bob Tway (65), Ken Duke (67) and Matt Jones (67) finished another stroke behind at 17 under.
Perry had a bogey-eagle-bogey-birdie stretch that dropped him from the lead and pulled him back into a tie with Austin at the 16th.
Austin moved ahead by curling a 9-footer in at the 16th, then fell back into a tie by missing a 13-foot putt for par on the next hole.
Perry missed a 34-footer for birdie on the 18th hole, giving Austin a chance to go back atop the leaderboard in the next group.
Austin, though, left himself with a 63-foot putt and he ran it past the hole. Then, he missed an 18-footer that gave Perry the lead.
Watson had a chance to force at least an extra hole despite a hooked tee shot by remarkably punching the ball onto the green to set up a makable putt that he was inches from making.
Perry may have locked up a spot on Ryder Cup team, a squad that has given the 47-year-old player incentive to play a heavy schedule to improve his chances of being in the marquee event in his home state of Kentucky.
His best shot of the week was at the par-4 14th, where his tee shot landed in sand and he chipped in for eagle from 30 yards.
But he lost the lead on the next hole when he plugged a shot into a greenside bunker, leading to a bogey that put Austin ahead.
Perry bounced back at 16 with a birdie, putting him in position to take advantage of Austins collapse and Watsons errant tee shot on the final hole.
Third-round leader Daniel Chopra (75) started the day with a two-shot lead that he lost quickly while going 4 over on the front nine.
U.S. Open runner-up Rocco Mediate closed with a 70 and finished 11 under, tied for 28th.
Perry moved into third place in the FedExCup standings, trailing Phil Mickelson and Tiger Woods, who missed the Buick Open because he had season-ending knee surgery after winning the U.S. Open. Jim Furyk, the top-ranked player in the lackluster field, and Justin Leonard closed with a 71s to finish tied for 36th and 55th respectively.