Boo Weekley began his professional career on the Developmental Players Tour (DP Tour) in Atlanta, Ga., a tour co-founded by Jack Slocum, father of fellow PGA golfer and friend Heath Slocum. Weekley attended high school with Slocum and they played together on the golf team. He lists Ben Hogan as his hero.

In 2008, Weekley successfully defended his title at the Verizon Heritage, and rose into the top 25 of the rankings. Weekley shot to prominence at the 2008 Ryder Cup, with a succession of virtuoso displays of superb golf including an emphatic 4&2 victory over Oliver Wilson in final day Singles play. The final day was also notable however when Weekley was filmed riding his driver "cowboy horse" style down the first fairway. 

In May 2013, Weekley won the Crowne Plaza Invitational at Colonial in Fort Worth, Texas.