Mixon started the 2016 season with 40 rushing yards, one rushing touchdown, and 77 receiving yards in a loss to Houston. In the next game against Louisiana–Monroe, he had 117 rushing yards. On October 1, against TCU, he had 105 rushing yards, one rushing touchdown, five receptions, and 70 receiving yards. On October 15, against Kansas State, he had 88 rushing yards, 34 receiving yards, one receiving touchdown, and threw a 26-yard touchdown. On October 22, he had the best statistical performance of his collegiate career with 31 carries for 263 rushing yards and two rushing touchdowns to go along with four receptions for 114 receiving yards and three receiving touchdowns in a win over Texas Tech. His career day against Texas Tech marked the first of six consecutive games with at least one rushing touchdown. On November 12, against Baylor, he had 124 rushing yards, one rushing touchdown, five receptions, and 63 receiving yards. He followed that up with 147 rushing yards and a rushing touchdown against West Virginia. On December 3, against Oklahoma State, he had 99 rushing yards, one rushing touchdown, two receptions, 19 receiving yards, and a receiving touchdown. On January 2, he had 91 rushing yards, two rushing touchdowns, five receptions, and 89 receiving yards in the victory over Auburn in the Sugar Bowl.