In his Eagles debut, Barkley rushed for 109 yards with two rushing touchdowns and a receiving touchdown in a 34–29 victory over the Green Bay Packers, becoming the first Eagles player to score three touchdowns in their debut with the team since Terrell Owens in 2004. His performance earned him NFC Offensive Player of the Week. The following week against the Falcons, Barkley rushed for 95 yards and caught four of five passes for 21 yards, but a late fourth-quarter drop that could have sealed the win for the Eagles proved costly as they lost 22–21. Barkley had 17 carries for 147 yards and two touchdowns in a 15–12 win over the Saints in Week 3.
In Week 7, Barkley made his return to MetLife Stadium against the Giants, rushing for 176 yards and a touchdown on 17 carries in a 28–3 victory over his former team. For his performance, he was declared NFC Offensive Player of the Week, for the second time this season. In Week 9, Barkley recorded 159 rushing yards and 199 scrimmage yards with two touchdowns, highlighted by a backwards hurdle over a Jaguars defender, in a 28–23 win, earning NFC Offensive Player of the Week. In Week 11 against the Commanders, Barkley finished with 198 total yards and rushed for two touchdowns in the fourth quarter as the Eagles won 26–18. Barkley continued his dominance the following week against the Los Angeles Rams, recording 255 rushing yards and 302 total yards, highlighted by multiple 70-yard touchdowns in the second half as the Eagles won 37–20, marking their seventh consecutive victory. His 255 rushing yards were the ninth-most in a single game in NFL history and the most in Eagles history.