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.
THE PLAYERS Championship: After beginning the final round of THE PLAYERS Championship three strokes off the lead, at 7-under 209, played his last six holes in 6-under to post a 6-under 66 and join a three-hole aggregate playoff with 2008 PLAYERS champion Sergio Garcia and Kevin Kisner. Finished birdie-par-birdie-eagle-birdie-birdie on Nos. 13-18 in regulation. Played Nos. 15-18 in a 5-under total of 11 strokes. The four-hole score of 11 set a new single-round low for the final four holes at TPC Sawgrass. Previously, seven players had finished with a score of 12 on the final four holes. When Garcia was eliminated after the aggregate playoff, Fowler and Kisner returned to the famed, par-3 17th for sudden death. Fowler converted a 4-foot, 8-inch putt for birdie to claim the title. Before his back-nine charge, his mother had made her way to the airport to leave town. A text message alerting her to her son's rally resulted in her immediate return to TPC Sawgrass in time to witness the win. With the victory, moved to ninth in the Official World Golf Ranking and No. 7 in The Presidents Cup standings.
On July 16, 2017, DeChambeau earned his first PGA Tour victory by winning the John Deere Classic by a single stroke over Patrick Rodgers. He carded a round of 65 in the final round to win his maiden title in his 40th start on tour. The win coming the week before, gained DeChambeau a place in the 2017 Open Championship, where he missed the cut after rounds of 76–77 (+13).
“I was literally thinking I’d need surgery but I talked to Greg, he was like no, no, no, don’t do any of that, we’re going to teach your body to tolerate the force. Usually when ligaments get torn or bones get broken or whatever it’s because the muscles aren’t functioning properly, so thats what I’ve been doing.” He’s been focusing on exercises that get him into “extreme positions of rotations and flexions” at which point he adds weight to build mental and physical tolerance in those positions.
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.
Lowry was the 2007 Irish Amateur Close Champion, defeating Niall Turner 4 & 3 in the final. While still an amateur in May 2009, he won The Irish Open on the European Tour, defeating Robert Rock on the third hole of a sudden death playoff. The win, on his tour début, made him just the third amateur to win on the European Tour, following Danny Lee earlier in the 2009 season, and Pablo Martín in 2007. Lowry shot a 62 to equal the lowest ever by an amateur on the circuit and led from the second round onwards.
Shell Houston Open: After opening with an 8-under 64 for a one-stroke lead on day one, added rounds of 71-67-70 to finish T3 at the Shell Houston Open. Erased a seven-shot deficit in the third round and started the final round three shots behind 54-hole leader Sung Kang, but a final-round 70 saw him finish four strokes behind winner Russell Henley. With 27 birdies on the week (tied for most with Henley), marked his most birdies in a single event.
Lowry received his first call-up to the full Australia squad for a friendly against the Netherlands in Sydney and the Asian Cup qualifier against Oman in Melbourne in October. He did not play in either match. On 11 May 2010 he was selected as part of Pim Verbeek's 30-man provisional squad for the 2010 World Cup, and travelled to South Africa, but was not included in the final 23-man World Cup squad. Lowry was named in Han Berger's 18-man squad for an August 2010 friendly against Slovenia, but he did not appear in the match.
Lowry made his professional debut in the 2009–10 UEFA Europa League in an away fixture at Rapid Vienna. On 17 September 2009, Lowry signed a three-month loan deal with Football League Championship side Plymouth Argyle. Lowry made his Plymouth Argyle debut on 19 September 2009, playing 90 minutes, in a 3–1 loss against Newcastle United. He played 13 league games for Plymouth during his loan spell, where he impressed many and was recalled by Villa who required Lowry's services as cover after some injuries to defenders.
With this win, he entered the Official World Golf Ranking as an amateur at No. 168 and reached a career high of sixth in the World Amateur Golf Ranking. Walker Cup captain Colin Dagleish described the win as "fairytale stuff", adding: "You'd have to say that Shane's victory was the biggest (of the three amateur wins). To win your own national Open is quite something. It was unbelievable, it really was." The win was only the second home victory since 1982 and the first since Pádraig Harrington in 2007. Harrington himself was also full of praise: "It's fabulous for Irish golf. You only have to look at the fact it is such a rarity for an amateur to win, such a rarity for an Irish player to win the Irish Open. So, on a lot of fronts, it is a big deal. It was very impressive."
Hyundai Tournament of Champions: Finished T6 in a Monday-start-Tuesday-finish event, the season-opening, 54-hole Hyundai Tournament of Champions. The event "started" twice during the regularly scheduled first round Friday and later Sunday, but both times PGA TOUR rules staff halted play due to unplayable windy conditions and subsequently voided all scores that had taken place. As the first player off the tee, he ended up hitting three "opening" shots of the season.