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 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.
Nationwide Tour Players Cup: Playoff runner-up to Derek Lamely at the Nationwide Children's Hospital Invitational. Started the final round five shots behind 54-hole leader Dave Schultz. Held the lead during much of the final round but suffered a bogey at the 72nd hole of regulation to drop into a tie with Lamely and force a playoff. Lost to Lamely when he failed to get up and down from a greenside bunker on the second extra hole, missing his par putt of 12 feet. Lamely rolled in a three-foot par putt to win.
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 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.
Lowry started his youth career with Australian club ECU Joondalup. He signed for Aston Villa in February 2005 along with fellow Australian Chris Herd. Lowry made nine appearances for Aston Villa Reserves in the 2006–07 season, mainly coming near the end of the campaign. Lowry was also part of the squad that won the HKFC International Soccer Sevens in May 2007. In June 2007, Lowry signed a 12-month deal to his contract.
On 27 January 2016, Lowry returned to Australia after a decade away from Australia when he signed a two-and-a-half-year deal with A-League side Perth Glory. Upon joining Perth Glory, Lowry said of the move, quoting: "I've got a lot of experience behind me now and I want to use it to guide the young lads who are in this young squad. I've spent 11 years in England and it's shaped my football over there and I'm really happy to be here and get stuck into the games"