Sam Burns was born in Shreveport, Louisiana, to Todd and Beth Burns. During his prep career at Calvary Baptist Academy, he was a three-time individual state champion. He was named AJGA Rolex Junior Player of the Year in 2014. Burns played college golf at Louisiana State University, where he won four tournaments in 15 collegiate starts during his sophomore season. 

In October 2017, Burns made his PGA Tour debut as a professional at the Sanderson Farms Championship.

On October 3, 2021, Burns won his second PGA Tour title at the Sanderson Farms Championship in Jackson, Mississippi. On March 20, 2022, Burns won his second consecutive Valspar Championship title, beating Davis Riley in a playoff. On May 29, 2022, Burns won the Charles Schwab Challenge after making a 38-foot birdie putt in a playoff against Scottie Scheffler. Burns overcame a seven stroke deficit to win, matching Nick Price in 1994 for largest comeback in a final round to win at Colonial Country Club.

Burns qualified for the U.S. team at the 2022 Presidents Cup; he tied two and lost three of the five matches he played.

In March 2023, Burns won the WGC-Dell Technologies Match Play, defeating Cameron Young 6 and 5 in the championship match.