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.
Hero World Challenge: After beginning the final round seven strokes out of the lead, closed with a tournament-record, personal-best 11-under 61 to win the Hero World Challenge by four strokes over Charley Hoffman. With a winning score of 18-under 270, won at the age of 28 years, 11 months and 20 days. His 61 topped the previous Hero World Challenge course record of 62, set by Albany resident Justin Rose during the final round in 2015. Prior to his 61, the previous low final-round score by a Hero World Challenge winner was 64, set on three occasions and most recently by Luke Donald in 2005. Opened his final round with seven birdies before making his first par on the par-4 eighth hole. No player has had as long a streak of birdies in an official PGA TOUR event to open a round since Joe Durant started round four of the 2005 Honda Classic with seven in a row. Added a birdie on the ninth hole to make the turn with an 8-under 28, turning a seven-stroke deficit into a two-stroke lead. His final round included 11 birdies, two more than his benchmark of nine birdies in official PGA TOUR events (final round of the Quicken Loans National in 2017). Finished the week at Albany Golf Club with 30 birdies, three more than his highest total in official PGA TOUR events (27 – 2017 Houston Open). Recorded his sixth top-six finish at the event in his sixth start (1/2017, T3/2016, 3/2015, T6/2014, T4/2012, T6/2011).
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.
Aberdeen Asset Management Scottish Open: Earned his second international victory when he captured the Aberdeen Asset management Scottish Open in come-from-behind fashion at Gullane GC in July. After a bogey on the 14th hole Sunday, fell two shots off the lead. He responded with three birdies over his final four holes to catch and pass American Matt Kuchar, who shot a final-round 68 to post the clubhouse lead at 11-under. He made a 9-foot birdie putt at No. 15, made a two-putt birdie at the par-5 16th, parred the 17th then hit his approach shot on the par-4 finishing hole to 2 feet for the tap-in birdie and the title. Joined seven other players who made the Scottish Open their first European Tour win.
All of DeChambeau's irons and wedges are cut to exactly the same length: 37.5 inches (95.3 cm). Their lie and bounce angle are also the same; only the lofts are different. In addition to the single-length concept, his clubs are unusual for their extremely upright lie angle.  DeChambeau keeps the club on the same plane throughout his swing and does not turn his wrists during his swing. In 2011, at the suggestion of his instructor Mike Schy, DeChambeau switched to JumboMax Grips, the largest grips commercially available. The larger grips allow DeChambeau to hold the grips in his palms and not his fingers.
Waste Management Phoenix Open: Claimed his second runner-up finish at the Waste Management Phoenix Open, one shot behind Hunter Mahan. Had birdie opportunities on the last three holes but unable to catch Mahan. Previously lost in a playoff to Troy Matteson just down the road at Grayhawk GC in the 2009 Frys.com Open. Had he won at TPC Scottsdale, would have become the first Sponsor Exemption to do so since Jason Gore (2005 84 Lumber Classic). Lee Westwood later won in June as a Sponsor Exemption at the St. Jude Classic presented by Smith & Nephew.
The Honda Classic: After beginning the final round of The Honda Classic with a four-stroke lead, posted a 1-over 71 to win by the same margin for his fourth career PGA TOUR title. It marked the first of five 54-hole leads he converted to victory. Opened with back-to-back 66s for the second consecutive year and posted a 65 in the third round to post the best 54-hole total since the event moved to PGA National in 2007 at 13-under 197. Seized the 54-hole lead with the widest margin of his career entering a final round. Turned in 2-over 37, but posted three birdies on the back nine to take command of the tournament. Despite bogeys on the 71st and 72nd holes, claimed his first victory since the 2015 Dell Technologies Championship. Finished the week second in Strokes Gained: Putting (7.392) and moved to 10th in the FedExCup standings and ninth in the Official World Golf Ranking, his first time in the top 10 since the 2016 BMW Championship.
In 2008, Fowler repeated as Sunnehanna Amateur champion. In the first round of the U.S. Open, Fowler shot a −1 (70) and was in a tie for 7th place. He was one of three amateurs to make the cut, along with Derek Fathauer and Michael Thompson. He ended the tournament tied for 60th. In October 2008 Fowler played on the Eisenhower Trophy team that finished second. He was the leading individual player.