He was selected by the Philadelphia Eagles in the second round of the 2019 NFL draft after playing college football for the Penn State Nittany Lions.

[4][5] Sanders saw a limited amount of playing time as a true freshman behind teammate Saquon Barkley.

[10] Sanders was presented with the 2018 Red Worrell Award, for the offensive player who best demonstrated exemplary conduct, loyalty, interest, attitude and improvement during spring practice.

On September 1, in his junior season debut against Appalachian State, he carried the ball 19 times, rushing for 91 yards and two touchdowns.

[8] On January 3, 2019, Sanders decided to declare for the NFL draft and forgo his senior season of college football.

[33] In the National Football Conference (NFC) Wild Card Round against the Seattle Seahawks, Sanders rushed 14 times for 69 yards in a 17–9 loss.

[36] In Week 5 against his hometown team, the Pittsburgh Steelers, Sanders rushed for 80 yards and two touchdowns, including a 74-yard score, during a 38–29 loss.

[38] In Week 14, against the New Orleans Saints, he had fourteen carries for 115 yards and two touchdowns, including a career-high 82-yard score, during the 24–21 win.

[40] Following the season, Sanders, along with Clyde Edwards-Helaire were selected to the playable Pro Bowl roster of the Madden 21 Video Game Numbers Challenge.

In the team's week 7 matchup against the Las Vegas Raiders, Sanders suffered a sprained ankle.

Sanders stepped back into a large role in the week 13 game against the New York Jets, as he carried the ball a season high 24 times for 120 yards.

[43] In week 15 against the Washington Football Team, Sanders recorded a season high 131 yards rushing on 18 carries.

[44] His hot streak came to an end during the Eagles' week 16 matchup against the New York Giants, Sanders broke a bone in his hand, which forced him to miss the final two games of the regular season.

[46] In Week 4, Sanders ran for 134 yards and two touchdowns, helping the Eagles move to 4–0 on the season during a 29–21 win over the Jacksonville Jaguars.

[52] In Super Bowl LVII, Sanders had seven carries for 16 yards in the Eagles 38–35 loss to the Kansas City Chiefs.

Sanders' struggles continued in Week 2 against the Saints on Monday Night Football, where he ran 14 times for a meager 43 yards in the 20-17 loss.