"That's when I realized, 'Wow, here I go.' I need to do something, either hold on to it or try to make a couple of more birdies," Weekley said. "I knew I was hitting the ball too well just to hold on."
With five consecutive pars after that, Weekly finished at 14-under 266 for a one-stroke victory over Matt Kuchar, the second- and third-round leader who had a closing 68.
Defending Colonial champion Zach Johnson, who also won at Hogan's Alley in 2010, shot 66 to finish third at 12 under for his first top-10 finish this season.
Both of Weekley's previous wins had been at Harbour Town, in 2007 and 2008.
In St. Louis, Kohki Idoki erased a five-stroke deficit against a fading Kenny Perry with room to spare, charging to a two-stroke victory in the Senior PGA Championship.
It was the third bitter final-round major tournament failure for the 52-year-old Perry, who led by three strokes with six holes to play but settled for a second-place tie with Jay Haas.
The 51-year-old Idoki closed with a 6-under 65 to finish at 11 under at Bellerive Country Club and win $385,000. Perry shot a 72.
In Paradise Island, Bahamas, Ilhee Lee won the rain-hampered Bahamas LPGA Classic for her first tour title. Lee made a clutch par putt on the second-to-last hole in a raging wind to keep a one-shot lead, and then closed with a birdie. That gave her a 5-under 42 for a two-shot win over Irene Cho.