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.
Presidents Cup: Closed out his second consecutive Presidents Cup appearance with a 6-and-4 victory over Emiliano Grillo, helping lead the United States to a 19-11 win over the International Team. Compiled a 3-0-1 overall record, highlighted by victories the first two days with teammate Justin Thomas in Foursomes (6 and 4 over Charl Schwartzel and Hideki Matsuyama) and Four-ball (3 and 2 over Branden Grace and Louis Oosthuizen).
Kolon Korea Open: Won his first tournament as a professional, the Kolon Korea Open on the OneAsia Tour, when he rolled to a six-stroke win over Rory McIlroy at Woo Jeong Hills CC in early October. He took control of the tournament in the third round when he shot an 8-under 63. He followed that with a 3-under 68 Sunday. The victory was worth a little under $250,000.
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.
Deutsche Bank Championship: Shot a final-round 3-under 68 to come from one shot back and defeat third-round leader Henrik Stenson at the Deutsche Bank Championship, good for his third career PGA TOUR victory. Earned the win at age 26 years, 8 months, 25 days in his 150th career start. Collected 2,000 points and moved from No. 22 to No. 3 in the FedExCup standings. Has come from behind to win all three of his PGA TOUR events, with his first two wins via playoffs (2012 Wells Fargo Championship and 2015 PLAYERS Championship). Became the sixth consecutive come-from-behind winner at TPC Boston.
BMW Championship: Entered the BMW Championship No. 36 in the FedExCup standings, with his T39 finish at Conway Farms outside Chicago leading to a final ranking of No. 38. Advanced to the TOUR Championship by Coca-Cola in 2012 (finished No. 28 in the FedExCup), but other three seasons led to near misses of cracking the top 30 in the FedExCup (No. 43 in 2011 and No. 32 in 2010).
At the 2016 U.S. Open at Oakmont Country Club near Pittsburgh, Lowry shot 65 (−5) in the third round for 203 (−7) and a four-stroke advantage over Dustin Johnson and Andrew Landry at the 54-hole stage. The 65 was Lowry's joint career best round at a major championship. Due to weather delays on Thursday, the third round was not completed until early on Sunday, and Lowry birdied two of his remaining four holes to extend his two stroke overnight lead to four. In the final round he was in contention for the title, within one shot of Dustin Johnson after 12 holes, before three consecutive bogeys on holes 14, 15 and 16 ended his chances. He finished the tournament tied for second place, with a final round score of 76.
At the first FedEx Cup playoff event, Fowler finished T52 at The Barclays in the last week in August. The following week he again finished T52 at the Deutsche Bank Championship, the second FedEx Cup playoff event, after carding a disappointing six-over par final round 77. At that point Fowler was positioned 37 in the FedEx Cup points standings and required a strong performance at the BMW Championship to qualify in the top thirty for The Tour Championship; a performance which eluded him, finishing in 48th place. In finishing 43rd in the FedEx Cup, Fowler earned a $132,000 bonus.
On 23 November 2011, Lowry was again loaned out to play in the Championship, this time to Millwall until 3 January 2012. He followed Aston Villa team-mate Nathan Baker who also signed on loan for Millwall two days earlier. Lowry made his Millwall debut three days later, where he played 90 minutes, in a 0–0 draw against Crystal Palace. His impressive display at Millwall soon earned a loan extension. Weeks later on 13 January 2012, Lowry was sent-off in the 22nd minutes after stamping on Nikola Žigić, which saw Millwall lose 6–0. Three years on after signing for Birmingham City, Lowry stated, quoting: "Whatever club I play for I fully commit to that club at the time. I play with my heart on my sleeve. Sometimes in the past I have gone overboard but I was a younger player then, I have learned a lot from these types of experiences. But I am an aggressive player, that’s the way I like to play and I can’t change the way I play. I will use my experience now and be a bit more clever."'