Lowry won for the first time as a professional in 2012, at the Portugal Masters in October. He shot a 67 to tie for the lead with the Englishman Ross Fisher, who made bogey on the final hole after missing a four-foot putt. The victory lifted Lowry back into the Official World Golf Ranking top 100 and made him eligible to compete in the WGC-HSBC Champions.
At the 2016 U.S. Open at Oakmont Country Club near Pittsburgh, Lowry shot 65 (−5) in the third round for 203 (−7) and a four-stroke advantage over Dustin Johnson and Andrew Landry at the 54-hole stage. The 65 was Lowry's joint career best round at a major championship. Due to weather delays on Thursday, the third round was not completed until early on Sunday, and Lowry birdied two of his remaining four holes to extend his two stroke overnight lead to four. In the final round he was in contention for the title, within one shot of Dustin Johnson after 12 holes, before three consecutive bogeys on holes 14, 15 and 16 ended his chances. He finished the tournament tied for second place, with a final round score of 76.
On August 26, 2018, he won The Northern Trust for his first playoff victory; in the process, he established a new record for the tournament when held at the Ridgewood Country Club, with a score of 266, besting the old Ridgewood record of 270, which was set in 2014 by Hunter Mahan. The following week, he won at the Dell Technologies Championship played at TPC Boston in Norton, Massachusetts, with a final score of −16, two shots clear of Justin Rose. This put him over 2000 points ahead of the second place player, Dustin Johnson, in the FedEx Cup rankings. This margin secured him top seeding at The Tour Championship, regardless of his finish at the BMW Championship. This also marked his fourth win on tour, third for the year, and second during the playoffs. At the Tour Championship, DeChambeau finished 19th out of 30 participants. As a result, he fell to 3rd in the FedEx Cup, winning $2,000,000.
DeChambeau made his PGA Tour debut as an amateur in June 2015 at the FedEx St. Jude Classic near Memphis, Tennessee, and finished in 45th place. He played in his first major championship at the U.S. Open at Chambers Bay, but missed the cut by four strokes. DeChambeau was unable to defend his NCAA title in 2016 after the SMU athletic department was handed a postseason ban by the NCAA. He decided to forgo his senior season to play in a number of events before turning professional. At the 2015 Australian Masters in November, DeChambeau was runner-up with John Senden and Andrew Evans, two shots behind the winner Peter Senior. He was the low amateur at the Masters in 2016 and tied for 21st place.