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.
In May 2012, Fowler won the Wells Fargo Championship in Charlotte on the first extra hole of a sudden-death playoff. Replaying the 18th hole, he defeated Rory McIlroy and D. A. Points with a birdie to gain his first PGA Tour win. Fowler shot a 69 (−3) in the final round to finish in a three-way tie after 72 holes at Quail Hollow Club. This win enabled Fowler to break the top-25 in the world, placing him at number 24. The following week at The Players Championship in Ponte Vedra Beach, Florida, Fowler played the final hole at −11 under par and had a birdie opportunity to bring him within one of leader and eventual winner Matt Kuchar. Fowler, however, pushed his putt to the right and finished in a tie for second, the fifth second-place finish of his career.
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.
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 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"