Franchitti, whose other victory this year came at the Indianapolis 500, won by 0.0681 seconds. The win helped Franchitti open up a 51-point lead over Tony Kanaan in the points race.
Scott Sharp was third, followed by Buddy Rice and Darren Manning. Eight of the top 10 drivers in the points standings, including Tony Kanaan and pole-winner Scott Dixon, were either involved in crashes or had mechanical trouble through the first 100 laps.
Franchitti went high to pass Rice on lap 151 and take the lead. He was quickly joined by Andretti, and the pair took a sizable lead over the field. Franchitti made his final pit stop with 35 laps to go, refusing to take new tires and opting for fuel only.
That decision proved critical for Franchitti in the race's final laps.
He opened his lead to more than five seconds shortly after pitting, but a caution flag allowed Andretti to close the gap. Franchitti hugged the bottom line, however, refusing to give Andretti space to make a move down the stretch.
Nonetheless, Andretti seems to have snapped out of his second-year slump. It was his best finish of the season, and it came after five races where he didn't crack the top 10.
Unseasonably cool weather left the drivers with cold tires coming out of pit stops, leading to three accidents that knocked out seven cars on the 0.875-mile (1.4-kilometer) track, which offered very little room to maneuver.
A multiple-car crash on the 99th lap changed the course of the race, knocking Danica Patrick, Sam Hornish Jr., A.J. Foyt IV and Kosuke Matsuura out of the race. Patrick made contact with Ed Carpenter, and Hornish Jr. and Foyt IV got tangled up in the mess. Carpenter's car spun around completely, but he continued.
"It's a cold day and the tires are really hard," Patrick said. "Unfortunately, this is just a lost race."
Helio Castroneves and Franchitti came out 1-2 after the first caution flag. Castroneves held the lead until he spun coming out of his first pit stop, 71 laps in. He rallied to finish eighth.
Kanaan's car fishtailed on lap 85, and Jeff Simmons caught his back tires as he tried to pass high. The accident ended the day for both Kanaan and Simmons.
"I was having a good run and ran into some turbulence, just got loose and hit the wall," Kanaan said.
Dixon's day was effectively over almost as soon as it began. He pitted right before the end of the first caution flag, which came out on the first lap, because of issues with his steering wheel. Dixon re-entered the race and finished 10th.
The first caution came out after Tomas Scheckter collided with Dan Wheldon when the back end of Wheldon's car flew open on the first lap. The accident knocked Scheckter out of the race and put Wheldon hopelessly behind.
Wheldon finished 11th.
"I am shocked. Everyone at Target Chip Ganassi Racing had worked so hard," Wheldon said. "It doesn't seem like anything is going my way right now."