In February 2010, Fowler finished second at the Waste Management Phoenix Open with a score of 15-under-par at the TPC of Scottsdale course. In June, Fowler notched his third PGA Tour runner-up finish at the Memorial Tournament in Dublin, Ohio. Fowler entered the final round in the lead, but shot a 73 to finish behind Justin Rose, who recorded his first PGA Tour victory. This performance took Fowler into the top 50 of the Official World Golf Ranking.
BMW Championship: After entering the final round of the BMW Championship in a second-place tie with Jason Day (five strokes behind Marc Leishman), recorded a 4-under 67 to finish T2, his 11th career runner-up on the PGA TOUR. Week was highlighted by a career-best, six consecutive birdies in the first round on Nos. 12-17. Chipped in from 64 feet on the 17th.
World Golf Championships-Accenture Match Play Championship: In his fourth consecutive start at the World Golf Championships-Accenture Match Play Championship, fought his way to the semifinals Sunday morning against Ernie Els. Got off to a hot start, leading for seven of the first nine holes. With a shift of momentum, Els battled back and won three consecutive holes (Nos. 10-12) to gain a 2-up lead. Following an eagle and par on Nos. 13 and 14, he squared up the match. An Els birdie-3 at No. 18 sent the match to extra holes. A birdie-3 at the 19th hole (No. 1) gave him the upset win over Els.
Lowry won for the first time as a professional in 2012, at the Portugal Masters in October. He shot a 67 to tie for the lead with the Englishman Ross Fisher, who made bogey on the final hole after missing a four-foot putt. The victory lifted Lowry back into the Official World Golf Ranking top 100 and made him eligible to compete in the WGC-HSBC Champions.
OHL Classic at Mayakoba: Birdied two of his last three holes at the OHL Classic at Mayakoba to fire a final-round 67 and finish in 2nd place, one shot back of Patton Kizzire. In his first start at the event, opened with a bogey-free, 6-under 65 to sit three back of Kizzire's lead. Followed with three-consecutives rounds of 67 in rounds two through four, resulting in a score of 18-under 266. Due to inclement weather Saturday, played his final two rounds on Sunday.
Lowry did not win on the European Tour from 2016 to 2018 but was joint runner-up in the 2017 DP World Tour Championship, Dubai and runner-up in the 2018 Andalucía Valderrama Masters. In January 2019 he won the Abu Dhabi HSBC Championship by a stroke from Richard Sterne. Lowry led by 3 strokes after three rounds but was two-over-par after 11 holes of his final round and dropped 4 shots behind Sterne. However he finished with 3 birdies in the final 7 holes, while Sterne had two bogeys, giving Lowry the victory.
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.
After a tie for fifth at the Masters in April, Fowler had his best finish of 2014 at the U.S. Open at Pinehurst No. 2 in North Carolina. Fowler was runner-up with Erik Compton at −1, best finishes for both at a major, but they were eight strokes behind champion Martin Kaymer. Fowler had another second-place finish, at the Open Championship at Royal Liverpool Golf Club in Hoylake, England. He began the final round six strokes behind Rory McIlroy and finished the day tied for second with Sergio García at −15, two strokes behind McIlroy. At the next major in August, the PGA Championship, Fowler, Phil Mickelson, Henrik Stenson, and McIlroy battled for the title on a rain-soaked Valhalla Golf Club, near Louisville. Despite holding the lead for a good portion of the day, Fowler tied for third. He was only the third player, along with Jack Nicklaus and Tiger Woods, to have finished in the top 5 in all four majors in one calendar year, but the first not to win (Jordan Spieth became the fourth player in 2015). Fowler had 10 top-10 finishes during the 2013–14 season. His 8th-place finish at The Tour Championship moved him to 10th in the world golf rankings.
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."
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.
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."'