In 2008, Fowler repeated as Sunnehanna Amateur champion. In the first round of the U.S. Open, Fowler shot a −1 (70) and was in a tie for 7th place. He was one of three amateurs to make the cut, along with Derek Fathauer and Michael Thompson. He ended the tournament tied for 60th. In October 2008 Fowler played on the Eisenhower Trophy team that finished second. He was the leading individual player.
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.
At the PGA Championship, Fowler carded 74-69-75-68 to finish with a six-over par total of 286, in a tie for 51st place. Early on the third day Fowler rocketed up the leaderboard with three birdies in the first five holes only to falter later in the round with two triple bogeys, effectively ending his hopes of a first major championship and PGA Tour win.
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.