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.
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.
On 27 January 2016, Lowry returned to Australia after a decade away from Australia when he signed a two-and-a-half-year deal with A-League side Perth Glory. Upon joining Perth Glory, Lowry said of the move, quoting: "I've got a lot of experience behind me now and I want to use it to guide the young lads who are in this young squad. I've spent 11 years in England and it's shaped my football over there and I'm really happy to be here and get stuck into the games"
Masters Tournament: Finished runner-up at the Masters, one stroke behind Patrick Reed, for his best result at the event. For the first time in eight starts at Augusta National, recorded four par-or-better rounds (70-72-65-67). Earned his third runner-up in a major (2nd/2018 Masters Tournament, T2/2014 The Open Championship, T2/2014 U.S. Open) and third top-five in the last four (2nd/2018 Masters Tournament, T5/2017 Open Championship, T5/2017 U.S. Open). With third-round 65, was one of just four players to post a bogey-free round during the week (Rory McIlroy/65, Jon Rahm/65, Si Woo Kim/65) with all four occurring in the final round.
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.
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.