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.
Lowry made his professional debut in the 2009–10 UEFA Europa League in an away fixture at Rapid Vienna. On 17 September 2009, Lowry signed a three-month loan deal with Football League Championship side Plymouth Argyle. Lowry made his Plymouth Argyle debut on 19 September 2009, playing 90 minutes, in a 3–1 loss against Newcastle United. He played 13 league games for Plymouth during his loan spell, where he impressed many and was recalled by Villa who required Lowry's services as cover after some injuries to defenders.
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."'
World Golf Championships-HSBC Champions: Came to the 72nd hole in need of a birdie to get into a playoff with Tim Clark and Bubba Watson at the World Golf Championships-HSBC Champions. Hit a 5-wood from the fairway that came up short and went in the water on the par-5. Made par after taking a penalty and finished T3 after a final-round 70 at Sheshan International GC in Shanghai.
“The switch was very easy. Even though he had won early in the year with another driver, he was not driving it good at all. He is very loyal to our team and our products that he came to us to find a new driver. He instantly loved the look of the Z 585 and once we started testing the numbers were exactly what he was looking for. His main comment about the driver is how his misses are minimal and he can hit all the shots he wants to.”
Waste Management Phoenix Open: Two weeks after the win in Abu Dhabi, made his eighth consecutive start in the Waste Management Phoenix Open, where he found himself three strokes off the lead after 54 holes. A final-round 4-under 67, capped off by a clutch birdie on the 72nd hole, forced sudden death with Hideki Matsuyama. On the fourth extra hole, the par-4 17th, an errant tee shot found the water hazard for the second time of the day. Matsuyama made par to win. Ranked second in Strokes Gained: Tee To Green and T1 in Strokes Gained: Total at TPC Scottsdale.
THE PLAYERS Championship: After beginning the final round of THE PLAYERS Championship three strokes off the lead, at 7-under 209, played his last six holes in 6-under to post a 6-under 66 and join a three-hole aggregate playoff with 2008 PLAYERS champion Sergio Garcia and Kevin Kisner. Finished birdie-par-birdie-eagle-birdie-birdie on Nos. 13-18 in regulation. Played Nos. 15-18 in a 5-under total of 11 strokes. The four-hole score of 11 set a new single-round low for the final four holes at TPC Sawgrass. Previously, seven players had finished with a score of 12 on the final four holes. When Garcia was eliminated after the aggregate playoff, Fowler and Kisner returned to the famed, par-3 17th for sudden death. Fowler converted a 4-foot, 8-inch putt for birdie to claim the title. Before his back-nine charge, his mother had made her way to the airport to leave town. A text message alerting her to her son's rally resulted in her immediate return to TPC Sawgrass in time to witness the win. With the victory, moved to ninth in the Official World Golf Ranking and No. 7 in The Presidents Cup standings.
Lowry made his Leyton Orient debut, playing as a left-back position, in the opening game of the season, which saw Leyton Orient lost 2–1 to Chesterfield. Since his debut, Lowry established himself in the left-back position in the first half of the season despite being sidelined with suspension and fitness concern that saw him out for two matches. Following his return to the first team, Lowry played in the central-defense between December and March until he dropped from the first team throughout March. Lowry went on to make his first team return throughout 2014–15 season, making thirty-four appearance in his first season at Leyton Orient.
The Open Championship: Playing in the final group Sunday for the second straight time in a major championship, made a solid bid for the title, at The Open Championship, with a final-round, 5-under 67. Along with Garcia, finished second to Rory McIlroy by two strokes. With his finish at Royal Liverpool GC, became the only player of the season to claim top-five finishes in the year's first three major championships. He also became the first player to claim top-10 finishes in a season's first three majors since Woods achieved the feat in 2005. His T2 at Royal Liverpool supplanted his previous-best Open Championship finish (in four starts) of T5 in 2011. Rounds of 69-69-68-67 made him the only player in the field to post all four rounds in the 60s.
The Barclays: Held a one-stroke lead over Patrick Reed after 54 holes at The Barclays in the FedExCup Playoffs, before a double bogey-birdie-bogey finish on Nos. 16-18 resulted in a T7 at 6-under 278 with Jason Kokrak and Ryan Moore. Fowler went bogey free at Bethpage Black from the 10th hole in round one until the 11th hole in the final round, a span of 55 holes. His 55-consecutive holes without a bogey became a personal best on the PGA TOUR, besting 53 from the 2010 Memorial Tournament. This streak also marked the longest recorded in Barclays history since hole information began in 1983. Ian Poulter had the longest with 45 in 2010. The finish marked his third top-10 showing in his last four starts in the event (T9/2013, T9/2014).