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.
In the 2013–14 season, Lowry suffered a minor thigh strain in the club's pre-season friendly. Despite this, Lowry remained in the first team under the new management of Steve Lomas until he received a straight red card after a foul on Will Hughes, in a 5–1 loss against Derby County on 14 September 2013. After serving a three match ban, Lowry remained on the bench without playing for four matches Lowry made his first team return on 2 November 2013 when he came on as a substitute for Scott Malone against Burnley. However, his return, after spending two months without playing, was a disastrous when he scored an own goal, which saw Millwall drew 2–2. After this, Lowry was out of the first team, demoted to the substitute bench between mid-November and mid-December until he made his return on 26 December 2013, in a 4–0 loss against Watford. On 28 January 2014, Lowry was sent-off for the second time this season in the late-minutes against Sheffield Wednesday after fighting with Giles Coke, who also was sent-off as well, with both side drew 1–1. After serving a four match ban, Lowry was in the first team throughout February and March until he suffered a foot injury that kept him out for the remainder of the season. Lowry went on to finish the 2013–14 season, making twenty-two appearance.
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).
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).
U.S. Open: Playing alongside eventual-champion Martin Kaymer in the final pairing Sunday, followed up his career-best round (3-under 67) in a U.S. Open with a final-round, 2-over 72 to remain T2 (the sixth runner-up finish of his career). It was his best performance in six U.S. Open starts (previous-best finish was a T10 in 2013). It was also his top major championship showing among his 18 starts (previous-best finishes were T5s at the 2011 Open Championship and the 2014 Masters). His pairing with the 29-year-old Kaymer was just the third final grouping at the U.S. Open since 1965 with two players in their 20s. The others were John Mahaffey (28) and Jerry Pate (22) in 1976 and Woods (26) and Sergio Garcia (22) in 2002.
Lowry elected to turn professional the week after his Irish Open triumph, meaning that he would miss out on the opportunity to play in the Walker Cup in September 2009. He made his professional début on 28 May at the European Open, where he shot 78 in the first round to end the opening day almost at the back of the field, and went on to miss the cut following a second round 73.