Weekley was a shot behind overnight leader Matt Kuchar when play began at Colonial Country Club but a string of birdies took him to the top of a crowded leaderboard that featured 22 players within five shots of the lead after the third round.
"It's unreal," Weekley told reporters. "Finally, I get to have my name up there. It don't get better than that."
The 39-year-old offset two early birdies with bogeys at the par-four fifth and par-four seventh holes but recovered with birdies at four of his next six holes on the way to a 14-under total of 266 that left him one shot ahead of Kuchar.
Kuchar (68) birdied the par-four 18th to finish alone in second place, a stroke ahead of former Masters champion Zach Johnson (66).
Scott Stallings (66), John Rollins (68) and Matt Every (69) were all a shot further back in a share of fourth place.
Jordan Spieth, the 19-year-old from Dallas who has played three of the last four years at Colonial, tied for seventh at 10-under.
"I'm extremely pleased with my round," Spieth said. "I could have very well won this golf tournament."
Weekley's last triumph before Sunday had come at the former Verizon Heritage, now known as the RBC Heritage, in 2008 before he was hit by injuries and a run of poor form.
Weekley, who helped the Unites States capture the Ryder Cup in 2008, showed flashes of his ball striking ability at Colonial, hitting more than 71 percent of his fairways and 75 percent of his greens in regulation.
His putting was also sharp and a 21-footer on the 13th green helped him to the long awaited win.
- Sports & Recreation
- Matt Kuchar
- Colonial Country Club