Lowry made his debut for the Glory on 30 January 2016, starting against Melbourne Victory. Lowry then scored his first Perth Glory goal on 20 February 2016 when he scored a header in the 41st minutes, to give Brisbane Roar a thrashing with a 6–3 win for Perth Glory. Throughout the 2015–16 season, Lowry established himself in the starting eleven and formed a central defense partnership with Alex Grant, as he made ten appearance for Perth Glory in his first half of the season.
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.
World Golf Championships-Accenture Match Play Championship: In his fourth consecutive start at the World Golf Championships-Accenture Match Play Championship, fought his way to the semifinals Sunday morning against Ernie Els. Got off to a hot start, leading for seven of the first nine holes. With a shift of momentum, Els battled back and won three consecutive holes (Nos. 10-12) to gain a 2-up lead. Following an eagle and par on Nos. 13 and 14, he squared up the match. An Els birdie-3 at No. 18 sent the match to extra holes. A birdie-3 at the 19th hole (No. 1) gave him the upset win over Els.
Immediately after the Masters in mid-April 2016, DeChambeau turned professional and signed a long-term agreement with Cobra-Puma Golf. He made his pro debut days later at the RBC Heritage in South Carolina and tied for fourth, earning over $259,000. The decision to turn professional meant the forfeiture of his exemptions to the U.S. Open at Oakmont and Open Championship at Royal Troon; he qualified his way into the U.S. Open, tied for fifteenth place for over $152,000, and improved his world ranking to 148.
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 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.
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.