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.
With this win, he entered the Official World Golf Ranking as an amateur at No. 168 and reached a career high of sixth in the World Amateur Golf Ranking. Walker Cup captain Colin Dagleish described the win as "fairytale stuff", adding: "You'd have to say that Shane's victory was the biggest (of the three amateur wins). To win your own national Open is quite something. It was unbelievable, it really was." The win was only the second home victory since 1982 and the first since Pádraig Harrington in 2007. Harrington himself was also full of praise: "It's fabulous for Irish golf. You only have to look at the fact it is such a rarity for an amateur to win, such a rarity for an Irish player to win the Irish Open. So, on a lot of fronts, it is a big deal. It was very impressive."
U.S. Open: Established the first-round lead at the U.S. Open with a 7-under 65 and was in the mix all week at Erin Hills. Followed with 73 to be one back through 36 holes. Third-round 68 had him two adrift headed into final round. Closed with even-par 72 to finish six back of Brooks Koepka at T5. In nine U.S. Open appearances, has advanced to the weekend five times and never broken par in the final round.
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.
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.