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.
Enjoyed a stellar rookie season, with seven top-10 finishes and a 32nd-place finish in the FedExCup standings that led to him winning PGA TOUR Rookie of the Year honors. Finished inside the top 30 on the money list to qualify for the Masters and the U.S. Open. Played in first three Playoff events, slipping from 21st to 32nd and out of the TOUR Championship.
BMW Championship: At No. 22 in the FedExCup standings heading into the third Playoffs event, the BMW Championship, he bogeyed No. 17 in a final-round even-par 72 to miss advancing to the TOUR Championship by half a point, finishing the season No. 31 in the FedExCup standings. Charl Schwartzel fired a final-round 8-under 64 to claim the No. 30 position.
Hero World Challenge: After beginning the final round seven strokes out of the lead, closed with a tournament-record, personal-best 11-under 61 to win the Hero World Challenge by four strokes over Charley Hoffman. With a winning score of 18-under 270, won at the age of 28 years, 11 months and 20 days. His 61 topped the previous Hero World Challenge course record of 62, set by Albany resident Justin Rose during the final round in 2015. Prior to his 61, the previous low final-round score by a Hero World Challenge winner was 64, set on three occasions and most recently by Luke Donald in 2005. Opened his final round with seven birdies before making his first par on the par-4 eighth hole. No player has had as long a streak of birdies in an official PGA TOUR event to open a round since Joe Durant started round four of the 2005 Honda Classic with seven in a row. Added a birdie on the ninth hole to make the turn with an 8-under 28, turning a seven-stroke deficit into a two-stroke lead. His final round included 11 birdies, two more than his benchmark of nine birdies in official PGA TOUR events (final round of the Quicken Loans National in 2017). Finished the week at Albany Golf Club with 30 birdies, three more than his highest total in official PGA TOUR events (27 – 2017 Houston Open). Recorded his sixth top-six finish at the event in his sixth start (1/2017, T3/2016, 3/2015, T6/2014, T4/2012, T6/2011).
In the 2012–13 season, Lowry regained his first team place, playing in the left-back and central defense positions until he missed one game after picking up a yellow card for the fifth time against Bristol City on 2 October 2012. After making his first team return as a left-back, Lowry then provided assist for the winning goal when he set up a goal for Chris Woods, in a 1–0 win against his former club, Leeds United on 18 November 2012. Lowry was then banned for two matches between 19 January 2013 and 25 January 2013 after picking up a yellow card for the tenth time this season. Lowry then He "curled a superb, dipping free-kick" to score from 35 yards (32 m) as Millwall beat Charlton Athletic 2–0 at The Valley on 16 March 2013. Lowry played in all matches in the run up to the Lions' FA Cup semi final against Wigan Athletic at Wembley, though he missed one match in the 4th round against his former club, Aston Villa. In late-April, Lowry was given a three match ban after being booked for the fifteenth time this season. Despite this, Lowry finished the 2012–13 season, making forty-five appearance and scoring once in all competitions.
After Lowry's loan spell at Leeds was coming to an end, on 11 May he signed a new two-year contract extension at Aston Villa. It was a remarkable few days for Lowry, he was promoted with Leeds, received a call up to Australia's World Cup Squad and on the same day he signed a new two-year deal with Villa. Despite signing a contract with the club, Leeds United was considering re-signing him for the second time ahead of the 2010–11 season, but never happened.
Fowler's first PGA Tour event as a professional was the Justin Timberlake Shriners Hospitals for Children Open where he finished tied for seventh. His second PGA Tour event was at the Frys.com Open played at Grayhawk Golf Club in Scottsdale, Arizona. He finished tied for second after losing to Troy Matteson in a three-way playoff that included Jamie Lovemark. Fowler's score of 18-under-par included a hole-in-one on the fifth hole in his final round. Fowler also notched an eagle in each of his four rounds.
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."
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.