Mixon played college football at Oklahoma, where he was a first-team All-Big 12, and was selected by the Cincinnati Bengals in the second round of the 2017 NFL draft.

Mixon attended Freedom High School in Oakley, California, where he played football and basketball for the Falcons.

[1] He was a three-year starter at running back for the Freedom High School Falcons football team.

In his first career game, Mixon had a 76-yard touchdown reception, the longest catch ever by a Sooner freshman running back.

[19] His career day against Texas Tech marked the first of six consecutive games with at least one rushing touchdown.

[23] After the 2016 season, Mixon decided to forgo his remaining two years of eligibility and enter the 2017 NFL draft.

[24] Coming out of college, some analysts and scouts graded Mixon as a first-round talent but projected him to be selected in the third or fourth round due to his prior history.

ESPN reported that on the weekend of the combine the Cincinnati Bengals met with Mixon in order for them to get a chance to talk with him extensively about his character.

On March 8, 2017, Mixon performed all of the combine tests and completed the positional workouts at Oklahoma's Pro Day.

[32] He was viewed as a first-round talent by some scouts, but several teams removed him from their draft board entirely due to character concerns after a prior assault on Amelia Molitor, a female student at Oklahoma.

New England Patriots owner Robert Kraft said, "While I believe in second chances and giving players an opportunity for redemption, I also believe that playing in the NFL is a privilege, not a right.

"[34] The editorial board of Cincinnati TV station WCPO criticized the draft pick and called for a boycott of the Bengals, writing, "Instead of buying a Bengals ticket this year, take the $50 or more you would have spent on that ticket and donate the money to a nonprofit that works to prevent violence against women.

[40] In Week 8, against the Indianapolis Colts, he recorded over 100 scrimmage yards (18 rushing and 91 receiving) for the first time in his career, 67 of them coming on a long run-after-catch play in the second quarter.

[65] In Week 6, he suffered a foot injury and missed the next three games before being placed on injured reserve on November 21, 2020.

[67] During Week 1 against the Minnesota Vikings, Mixon finished with 127 rushing yards and a touchdown as the Bengals won 27–24 in overtime.

[88] He moved into third place for the Bengals' franchise rushing leader, behind James Brooks and Corey Dillon.

[92] In his Texans debut against the Colts on September 8, Mixon recorded his third-highest career rushing output in a single game as he finished with 159 yards with a touchdown in a 29–27 win, earning AFC Offensive Player of the Week.

[102] Mixon entered an Alford plea to a misdemeanor assault charge in October 2014 for punching Amelia Molitor, breaking bones in her face and resulting in hospitalization and surgery.

Molitor required surgery after the incident, as the punch and resulting fall had broken four bones in her face.

[104] Mixon received a one-year deferred sentence and was ordered to undergo counseling along with 100 hours of community service.

The alleged incident was said to have happened one day before the Bengals faced the Buffalo Bills in the AFC Divisional playoff game.

[106] On February 3, 2023, less than 24 hours after the warrant was issued the aggravated menacing charge against Mixon was dismissed, per the request of The Hamilton County Prosecutor's Office.

According to WCPO-TV, a prosecutor told county judge Curt Kissinger, "We need additional investigation before we would move forward with this case."

[107] On April 7, 2023, the Cincinnati Police Department publicly announced the criminal charge against Mixon had been refiled.

[108] On August 17, 2023, Mixon was found not guilty and acquitted of the charges following a four-day trial in Hamilton County Municipal Court.

[109] On March 6, 2023, the Hamilton County sheriff department responded to a "shots fired" call at Mixon's home.

[110] An injured child was found on the scene and transported to Cincinnati Children's Hospital Medical Center with non-life-threatening injuries.