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.
THE PLAYERS Championship: A week after collecting his first PGA TOUR victory, nearly became the first player since David Duval (1997) to post first two TOUR victories in back-to-back weeks, finishing T2 at THE PLAYERS, two strokes behind winner Matt Kuchar. Holed a birdie attempt from 21 feet, 7 inches on the par 3 17th in the final round to move to 11-under but couldn't convert a 7-foot, 7-inch birdie on No. 18 that would have given him the clubhouse lead at 12-under. Recorded his fifth career runner-up finish on TOUR in his 73rd start. His T2 performance came in his third start at THE PLAYERS and first in which he made the 36-hole cut. Moved into contention with a 66 in the third round, a career low at TPC Sawgrass. Entered the final round three shots off the 54-hole pace.
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).
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.
Wells Fargo Championship: Made birdie-3 on the first extra hole (No. 18) to defeat Rory McIlroy and D.A. Points at the Wells Fargo Championship for his first TOUR win. Improved to 1-1 in playoffs (lost to Troy Matteson, 2009 Frys.com Open). The playoff was the fifth at the Wells Fargo Championship. At the age of 23 years, 4 months, 23 days, became the third player to make the Wells Fargo Championship his first PGA TOUR win (Anthony Kim in 2008 and McIlroy in 2010). Became the third-youngest winner of the event, behind McIlroy (20 years, 11 months, 28 days) and Kim (22, 10, 15). His win came in his 72nd start on TOUR and was his 16th top-10 finish. Opening-round 66 is the lowest start by a winner of the Wells Fargo Championship. Won in his third start at the Wells Fargo Championship (T6 in 2010 and T16 in 2011).
Aberdeen Asset Management Scottish Open: Earned his second international victory when he captured the Aberdeen Asset management Scottish Open in come-from-behind fashion at Gullane GC in July. After a bogey on the 14th hole Sunday, fell two shots off the lead. He responded with three birdies over his final four holes to catch and pass American Matt Kuchar, who shot a final-round 68 to post the clubhouse lead at 11-under. He made a 9-foot birdie putt at No. 15, made a two-putt birdie at the par-5 16th, parred the 17th then hit his approach shot on the par-4 finishing hole to 2 feet for the tap-in birdie and the title. Joined seven other players who made the Scottish Open their first European Tour win.
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.