Simpson was born James Frederick Webb Simpson on August 8, 1985 in Raleigh, North Carolina.
Simpson played high school golf at Broughton High before his collegiate golf career at Wake Forest University on the Arnold Palmer Scholarship. He was a three-time All-American and the ACC Player of the Year in 2008. He played on the victorious 2007 Walker Cup team and the 2007 Palmer Cup team.
After turning professional in June 2008, Simpson played on the PGA Tour and Nationwide Tour on sponsor's exemptions. He recorded two runner-up finishes on the Nationwide Tour. He then competed in the PGA Tour's qualifying school and finished T7 to earn his Tour card for 2009. He had a successful start to his rookie year with a 5th place finish at the Bob Hope Classic and a 9th place finish at the Sony Open in Hawaii. He ended the season with four top 10 finishes and retained his tour card ranked 70th on the money list.
Simpson had a chance to win his first PGA Tour title at the 2011 Transitions Championship. Simpson won his first PGA Tour title at the Wyndham Championship in Greensboro, North Carolina, his home state, on August 21, 2011. Simpson won his second tournament of the 2011 PGA Tour season and of his career, at the second FedEx Cup playoff event, the Deutsche Bank Championship.
Simpson opened the 2012 season by making 10 consecutive cuts. During this time he recorded four top-10 finishes. On June 17, he won the U.S. Open at the Olympic Club in San Francisco.