In his freshman year at UCLA, Cantlay won four tournaments and won the Haskins Award as the most outstanding college golfer in 2011. He was also named the Golf Coaches Association of America (GCAA) Division I Jack Nicklaus National Player of the Year. Cantlay also won the Phil Mickelson Award as the GCAA National Freshman of the Year in addition to being the Pac-10 Player of the Year and Freshman of the Year. He also won the Mark H. McCormack Medal as the top-ranked amateur in the world at the end of the 2011 season. This award earned him an invitation to the 2012 Open Championship.

On March 23, 2011 he became world number 1 in the World Amateur Golf Ranking. He holds the records for most consecutive weeks at number one, 54, and held the record for most total weeks at number one, 55, until Jon Rahm eclipsed him in 2016.

On August 6, Cantlay lost to Ethan Tracy in the Western Amateur final at the North Shore Country Club in Glenview, Illinois. On August 28, at Erin Hills in Erin, Wisconsin, he lost in the final of the U.S. Amateur to Kelly Kraft. Making the finals earned him a spot in the 2012 Masters Tournament, where he finished in a tie for 47th, making him the low amateur.

In June 2012, Cantlay decided to forgo his final two years of college to turn professional. The decision to go professional meant forfeiting his spot at the 2012 Open Championship. His professional debut was at the 2012 Travelers Championship, where he missed the cut. Prior to the Travelers, Cantlay announced he would be signing with Mark Steinberg and Excel Sports Management Group, the same management as Tiger Woods. Cantlay was the number one amateur in the world before turning pro, holding the top spot for a record 55 weeks. At the time, he was also ranked 415th in the Official World Golf Ranking. He earned his first professional paycheck at AT&T National, finishing in a tie for 66th. The following week he finished in a tie for 38th at the Greenbrier Classic.

Cantlay earned his first professional win at the 2013 Colombia Championship, an event on the Web.com Tour. He played in the Web.com Tour Finals and finished 11th to earn his PGA Tour card for 2014. In the 2013–14 season he played only five events due to a back injury and was granted an 11-event medical extension. He played in just one tournament the following season, in late 2014, but didn’t play at all in 2015 or 2016. As of the start of the 2017 season, ten starts remained on his medical extension.

In February 2016, his caddie, Chris Roth, was killed in a hit-and-run accident in Newport Beach, California while Roth and Cantlay were out on the town. Roth had been a high school teammate of Cantlay’s and had caddied for him in his amateur and professional career.

In his second start of the 2018 season, on November 5, 2017, Cantlay won his first PGA Tour title at the Shriners Hospitals for Children Open on the second extra hole of a three-man playoff. It was the second consecutive year in which his second start of the season secured his Tour card for the following season.

On November 4, 2018, Cantlay narrowly missed defending his title at the Shriners Hospitals for Children Open. He finished second by one stroke to champion Bryson DeChambeau.

In 2019, he finished tied for third place at the PGA Championship behind winner, Brooks Koepka. Two weeks later he won the Memorial Tournament in Dublin, Ohio, a result that lifted him into the world top-10 for the first time. Cantlay shot a final round of 64 to come from four strokes behind the 54-hole leader Martin Kaymer and win his second PGA Tour title.

In October 2019, Cantlay again narrowly missed winning the Shriners Hospitals for Children Open. He lost a playoff to Kevin Na on the second playoff hole.

In December 2019, Cantlay played on the U.S. team at the 2019 Presidents Cup at Royal Melbourne Golf Club in Australia. The U.S. team won 16–14. Cantlay went 3–2–0 and won his Sunday singles match against Joaquín Niemann.

In October 2020, Cantlay won the Zozo Championship at Sherwood Country Club in Thousand Oaks, California. The event normally takes place in Japan but was moved to California in 2020 due to the COVID-19 pandemic.