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.
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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.
THE PLAYERS Championship: A week after collecting his first PGA TOUR victory, nearly became the first player since David Duval (1997) to post first two TOUR victories in back-to-back weeks, finishing T2 at THE PLAYERS, two strokes behind winner Matt Kuchar. Holed a birdie attempt from 21 feet, 7 inches on the par 3 17th in the final round to move to 11-under but couldn't convert a 7-foot, 7-inch birdie on No. 18 that would have given him the clubhouse lead at 12-under. Recorded his fifth career runner-up finish on TOUR in his 73rd start. His T2 performance came in his third start at THE PLAYERS and first in which he made the 36-hole cut. Moved into contention with a 66 in the third round, a career low at TPC Sawgrass. Entered the final round three shots off the 54-hole pace.
Fowler is one of four golfers in the "Golf Boys" group along with fellow PGA Tour players Ben Crane, Bubba Watson and Hunter Mahan. The Golf Boys released a YouTube video of the song "Oh Oh Oh" on the eve of the 2011 U.S. Open. Farmers Insurance is donating $1,000 for every 100,000 views of the video. The charitable proceeds will support both Farmers and Ben Crane charitable initiatives.
BMW Championship: Entered the BMW Championship No. 36 in the FedExCup standings, with his T39 finish at Conway Farms outside Chicago leading to a final ranking of No. 38. Advanced to the TOUR Championship by Coca-Cola in 2012 (finished No. 28 in the FedExCup), but other three seasons led to near misses of cracking the top 30 in the FedExCup (No. 43 in 2011 and No. 32 in 2010).
On 23 November 2011, Lowry was again loaned out to play in the Championship, this time to Millwall until 3 January 2012. He followed Aston Villa team-mate Nathan Baker who also signed on loan for Millwall two days earlier. Lowry made his Millwall debut three days later, where he played 90 minutes, in a 0–0 draw against Crystal Palace. His impressive display at Millwall soon earned a loan extension. Weeks later on 13 January 2012, Lowry was sent-off in the 22nd minutes after stamping on Nikola Žigić, which saw Millwall lose 6–0. Three years on after signing for Birmingham City, Lowry stated, quoting: "Whatever club I play for I fully commit to that club at the time. I play with my heart on my sleeve. Sometimes in the past I have gone overboard but I was a younger player then, I have learned a lot from these types of experiences. But I am an aggressive player, that’s the way I like to play and I can’t change the way I play. I will use my experience now and be a bit more clever."'
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.
The Open Championship: Enjoyed his best finish among seven major championship starts, with a T5 at The Open Championship at Royal St. George's. Opened with three par-or-better rounds to enter the final round three strokes behind Darren Clarke. Closed with a 2-over 72 in windy conditions to finish tied with fellow Americans Chad Campbell and Anthony Kim.
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.
After a tie for fifth at the Masters in April, Fowler had his best finish of 2014 at the U.S. Open at Pinehurst No. 2 in North Carolina. Fowler was runner-up with Erik Compton at −1, best finishes for both at a major, but they were eight strokes behind champion Martin Kaymer. Fowler had another second-place finish, at the Open Championship at Royal Liverpool Golf Club in Hoylake, England. He began the final round six strokes behind Rory McIlroy and finished the day tied for second with Sergio García at −15, two strokes behind McIlroy. At the next major in August, the PGA Championship, Fowler, Phil Mickelson, Henrik Stenson, and McIlroy battled for the title on a rain-soaked Valhalla Golf Club, near Louisville. Despite holding the lead for a good portion of the day, Fowler tied for third. He was only the third player, along with Jack Nicklaus and Tiger Woods, to have finished in the top 5 in all four majors in one calendar year, but the first not to win (Jordan Spieth became the fourth player in 2015). Fowler had 10 top-10 finishes during the 2013–14 season. His 8th-place finish at The Tour Championship moved him to 10th in the world golf rankings.
The Open Championship: Playing in the final group Sunday for the second straight time in a major championship, made a solid bid for the title, at The Open Championship, with a final-round, 5-under 67. Along with Garcia, finished second to Rory McIlroy by two strokes. With his finish at Royal Liverpool GC, became the only player of the season to claim top-five finishes in the year's first three major championships. He also became the first player to claim top-10 finishes in a season's first three majors since Woods achieved the feat in 2005. His T2 at Royal Liverpool supplanted his previous-best Open Championship finish (in four starts) of T5 in 2011. Rounds of 69-69-68-67 made him the only player in the field to post all four rounds in the 60s.
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).
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Waste Management Phoenix Open: Won fifth PGA TOUR title at the Waste Management Phoenix Open in his 220th career start at the age of 30 years, 1 month, 21 days. Began the final round with a four-shot lead and won by two strokes after recording a double bogey and triple bogey en route to a closing 3-over 74. Became the first player since 1983 to win with both a double bogey and triple bogey or worse in the final round. Triple bogey came at No. 11 at TPC Scottsdale after he chipped his ball into the water and received an additional penalty when the ball rolled back into the water after he had placed it back into play. Marked the second time of seven occasions he converted a 54-hole lead to victory.
Lowry missed the first three cuts of his professional career, but had his first payday on 5 July, when he finished 50th at the Open de France ALSTOM. He had his best professional result in November 2009, when he finished 3rd in the Dunlop Phoenix Tournament in Japan. In January 2010, Lowry finished in fourth place in the Abu Dhabi Golf Championship, moving him into the top-100 of the Official World Golf Ranking.