He played college football for the Oklahoma Sooners, and was selected by the Washington Redskins in the fourth round of the 2017 NFL draft.

Perine was born and raised in Jackson, Alabama, but later moved with his family to Pflugerville, Texas, where he attended Hendrickson High School as a member of their football and track and field teams.

[10] In his first career game, he rushed for 77 yards on 13 carries with one touchdown in a victory over Louisiana Tech.

[12][13] He rushed for 200 yards a second time, gaining 213 on 25 carries along with three touchdowns against Texas Tech on November 15.

[19] In the next game, a 2OT win over the #23 Tennessee Volunteers at Neyland Stadium, he had 78 rushing yards and a receiving touchdown.

[35] After the season, Perine decided to forgo his senior year and enter the 2017 NFL draft.

[36] The Washington Redskins selected Perine in the fourth round (114th overall) of the 2017 NFL Draft.

[41] Perine joined a committee backfield of Chris Thompson, Robert Kelley, and Mack Brown.

[42] Despite being granted the majority of the team's rushes, he had fewer yards than either Thompson (78) or Kelley (77).

[43] In Week 3 against the Oakland Raiders, he again led the team in carries with 19 but for only 49 yards, and was moved back into a supporting role.

[44] After nine rushes for 35 yards and a 25-yard reception in Week 9, Perine moved back to starting following injuries to both Thompson and Kelley.

[62] In the AFC Championship against the Kansas City Chiefs, he had a 41-yard touchdown reception from Joe Burrow in the second quarter.

[68] On August 28, 2024, the Kansas City Chiefs signed Perine to a one-year, $1.5 million contract.

[70] He played in Super Bowl LIX, recording one carry for eight yards in the 40–22 loss to the Eagles.

[71] During his time in high school and Oklahoma, Perine was noted for his acts of great physical strength, such as helping lift a car to help a fellow student who did not have a car jack in order to change a flat tire.

[72] Jerry Schmidt, strength coach of the Sooners, stated that he could often out bench press most of the team's linemen, with his max being 440 lbs.