He played college football for the Notre Dame Fighting Irish and was selected by the Pittsburgh Steelers in the second round of the 2020 NFL draft.

[11] Claypool took over as Notre Dame's number one receiver his senior year in 2019, a season in which he caught 66 passes for 1,037 yards and 13 touchdowns.

[19] On September 20, during Week 2 against the Denver Broncos, Claypool finished with three receptions for 88 receiving yards, including an 84-yard touchdown, as the Steelers won 26–21.

[27] In the Wild Card round of the playoffs against the Cleveland Browns, Claypool recorded 5 catches for 59 yards and two touchdowns during the 48–37 loss.

The celebration, which was noted by CBS Sports to take "at least 5 seconds" off the clock, wound up being costly as the Steelers could not score in time and lost the game.

[29] Overall, Claypool played in 15 games in 2021, starting 13, and posted similar catch and yardage totals compared to his rookie season, though he only caught two touchdowns.

[30][31] Claypool was traded to the Chicago Bears on November 1, 2022, in exchange for their second-round pick (32nd overall; later used to select Joey Porter Jr.) in the 2023 NFL draft.

[38][39] The team had instructed him to remain at home the following week as well, while they won in a Thursday Night Football road game (their first win since October 24, 2022) against the Washington Commanders.