Claypool played in 12 games as a true freshman at Notre Dame in 2016. He finished the season with five receptions for 81 yards and led the team in special teams tackles with 11.[8] As a sophomore in 2017, he started eight of 12 games, recording 29 receptions for 402 yards and two touchdowns.[9][10] As a junior in 2018, Claypool started 12 of 13 games, finishing second on the team with 50 receptions for 639 yards and four touchdowns.[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.[12][13]
Claypool was selected by the Pittsburgh Steelers in the second round, 49th overall, in the 2020 NFL draft as the team's first selection.[16] Although eligible as a Canadian and rated as the No. 2 prospect, Claypool went undrafted in the 2020 CFL Draft.[17][18]
On July 22, 2020, the Pittsburgh Steelers signed Claypool to a four-year, $6.61 million rookie contract that includes $3.28 million guaranteed and a signing bonus $2.37 million.[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.[20] In Week 5, against the Philadelphia Eagles, Claypool finished with 110 receiving yards and four total touchdowns (three receiving & one rushing), both career highs, as the Steelers won 38–29. With his Week 5 effort, Claypool became the first Steelers rookie in franchise history to score four touchdowns in a game, and the first Steeler since Roy Jefferson in 1968 to do so.[21] His performance helped the team start out with a 4–0 record for the first time since 1979.[22] On October 14, Claypool was named the AFC Offensive Player of the Week for his performance in Week 5.[23] In Week 10, against the Cincinnati Bengals, he had four receptions for 56 receiving yards and two receiving touchdowns in their 36–10 victory.[24]
Claypool had a successful rookie year, catching 62 passes for 873 yards and 9 touchdowns, in addition to two rushing touchdowns.[25][26] He was named to the PFWA All-Rookie Team.[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.[28]
The following season, during a game against the Minnesota Vikings, Claypool, who had already been pulled from the game earlier for poking Vikings cornerback Bashaud Breeland in the face, received criticism after celebrating a first down reception while the Steelers were trailing 36–28 with just 30 seconds left in the game. 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.[26] He missed two games due to injuries to his hamstring and toe, respectively.[30][31]
He was intensely criticized for a low-effort performance in the Bears' 2023 season opener against the Green Bay Packers.[34] It was reported on September 17 that Claypool had apologized for this to his teammates and coaches.[35] By week 4, Claypool expressed frustration with the Bears and stated that he did not believe the coaching staff put him in a position to succeed.[36] The Bears deactivated him before their week 4 matchup against the Broncos, and activated Equanimeous St. Brown in his place.[37] Claypool had been told by the team to stay home during the Denver game, and was later told not to return to their facility while they searched for a trade partner the following week.[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.[40]
As a Bear, he appeared in ten games, recording 191 receiving yards and one touchdown on 18 receptions.[41]
Miami Dolphins
On October 6, 2023, the Bears traded Claypool and a seventh-round selection in the 2025 NFL draft to the Miami Dolphins in exchange for a sixth-round selection in the 2025 NFL Draft.[42] In Week 8 vs. the New England Patriots, Claypool caught 1 pass for 15 yards, his first reception with the Dolphins.
Buffalo Bills
On May 3, 2024, Claypool signed a one-year contract with the Buffalo Bills.[43] On August 12, Claypool was placed on injured reserve with a toe injury.[44] He was released with an injury settlement on August 15.