Smith was selected by the Philadelphia Eagles with the tenth overall selection in the 2021 NFL draft, who had traded up two spots with the Dallas Cowboys to select him. He was the third wide receiver taken in the draft after Ja'Marr Chase and Jaylen Waddle.
Smith had five games going over the 100-yard mark in the 2022 season. Smith finished his second season catching 95 passes for 1,196 yards and seven touchdowns. In the Divisional Round against the New York Giants, he had a receiving touchdown in the 38–7 victory. In the NFC Championship against the San Francisco 49ers, Smith recorded a one-handed 29-yard reception on fourth down on the Eagles' opening drive. The catch was likely to have been ruled incomplete upon further review, but the Eagles were able to get a quick snap off before it could be challenged. The catch set up the Eagles with first-and-goal, which they were able to score a touchdown on. The Eagles won the game 31–7. In Super Bowl LVII against the Chiefs, Smith had seven catches for 100 yards in the 38–35 loss. He was ranked 100th by his fellow players on the NFL Top 100 Players of 2023.