Lowry won for the first time as a professional in 2012, at the Portugal Masters in October. He shot a 67 to tie for the lead with the Englishman Ross Fisher, who made bogey on the final hole after missing a four-foot putt. The victory lifted Lowry back into the Official World Golf Ranking top 100 and made him eligible to compete in the WGC-HSBC Champions.
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.
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.
Frys.com Open: At the Frys.com Open in Scottsdale, Ariz., reached a three-way playoff with Jamie Lovemark and eventual-winner Troy Matteson. Began the final round four strokes behind Matteson, but played his first five holes in 5-under, punctuated by a hole-in-one from 211 yards at the par-3 fifth hole. After finishing T2 in the playoff, he had recorded all eight of his professional rounds in the 60s. Thanks to the T7 in Las Vegas at the Justin Timberlake Shriners Hospitals for Children Open and T2 finish at Grayhawk GC, he surpassed No. 150 from the 2008 money list, earning special temporary membership on TOUR for the remainder of the season.
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."'
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.
Lowry started the 2018-19 season with partial status after finishing 140th in the FedEx Cup. He moved into a share of the 36-hole lead at the 2019 Open Championship at Royal Portrush, after successive opening rounds of 67. He was tied at eight under with J. B. Holmes. Lowry then shot a 63 for a new course record to lead by four strokes at the end of the third round. He won the tournament by six shots ahead of Tommy Fleetwood.
After Lowry's loan spell at Leeds was coming to an end, on 11 May he signed a new two-year contract extension at Aston Villa. It was a remarkable few days for Lowry, he was promoted with Leeds, received a call up to Australia's World Cup Squad and on the same day he signed a new two-year deal with Villa. Despite signing a contract with the club, Leeds United was considering re-signing him for the second time ahead of the 2010–11 season, but never happened.
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.