Masters Tournament: Finished runner-up at the Masters, one stroke behind Patrick Reed, for his best result at the event. For the first time in eight starts at Augusta National, recorded four par-or-better rounds (70-72-65-67). Earned his third runner-up in a major (2nd/2018 Masters Tournament, T2/2014 The Open Championship, T2/2014 U.S. Open) and third top-five in the last four (2nd/2018 Masters Tournament, T5/2017 Open Championship, T5/2017 U.S. Open). With third-round 65, was one of just four players to post a bogey-free round during the week (Rory McIlroy/65, Jon Rahm/65, Si Woo Kim/65) with all four occurring in the final round.
Immediately after the Masters in mid-April 2016, DeChambeau turned professional and signed a long-term agreement with Cobra-Puma Golf. He made his pro debut days later at the RBC Heritage in South Carolina and tied for fourth, earning over $259,000. The decision to turn professional meant the forfeiture of his exemptions to the U.S. Open at Oakmont and Open Championship at Royal Troon; he qualified his way into the U.S. Open, tied for fifteenth place for over $152,000, and improved his world ranking to 148.
On June 3, 2018, DeChambeau won the Memorial Tournament in Dublin, Ohio, in a sudden-death playoff against Kyle Stanley and An Byeong-hun, after the three finished regulation play tied at −15. After Stanley bogeyed the first hole of sudden death, DeChambeau then proceeded to win with a birdie on the second hole, giving him his second win on the tour.
In June 2015, he became the first SMU Mustang to win the NCAA individual championship, recording a score of 280 (−8) to win by one stroke. In August, he won the U.S. Amateur title, defeating Derek Bard 7 & 6 in the 36-hole final. He became the fifth player to win both the NCAA and U.S. Amateur titles in the same year, joining Jack Nicklaus (1961), Phil Mickelson (1990), Tiger Woods (1996), and Ryan Moore (2004).
PGA Championship: Finished T3 and two strokes behind McIlroy at the PGA Championship in his 20th major championship start, with T19 in 2013 the previous-best finish in four prior PGA Championship starts. Became the first to claim top-five finishes in all four majors since Woods in 2005. Since 1934, is just the third player to perform the feat, joining Woods in 2000 and 2005 and Jack Nicklaus in 1971 and 1973. Played all four majors in 32-under, with McIlroy second on the list, at 27-under.
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.