As a true freshman at Alabama in 2015, Payne had 13 tackles and half a sack. As a sophomore in 2016, he had 36 tackles and 1.5 sacks. In the National Championship Game against Clemson, he recorded five tackles and a half sack.

As a junior in 2017, Payne was named the defensive MVP of both postseason games that Alabama played. In the Sugar Bowl versus Clemson, he intercepted a ball and scored an offensive receiving touchdown on the resulting drive. In the National Championship Game against Georgia, Payne had six tackles to help lead Alabama to their second national championship in three seasons. After his junior year, Payne declared his intentions to enter the 2018 NFL Draft. During his time at Alabama, Payne’s given name was commonly misspelled as Da’Ron, which he requested to change back to the correct Daron for his professional career.

Payne was drafted by the Washington Redskins in the first round (13th overall) of the 2018 NFL Draft. On May 10, 2018, Payne signed a four-year contract worth US$14.4 million featuring a $8.56 million signing bonus. He recorded his first career sack in Week 3 against the Green Bay Packers. He finished his rookie season with 56 tackles, five sacks, a forced fumble and fumble recovery, and was named to the 2018 PFWA All-Rookie Team as a result.