The
Buffalo Bills selected Knox in the third round with the 96th overall pick in the
2019 NFL draft. Knox signed his rookie contract with the team on June 14, 2019. On September 22, 2019, Knox caught his first NFL touchdown from
Josh Allen against the
Cincinnati Bengals in Week 3. He had a hand in the Bills' game-winning drive, catching another reception from Allen for 49 yards and running over two Bengals defenders along the way to set up a touchdown run by
Frank Gore. Knox finished with three receptions for 67 yards and a touchdown as the Bills won 21–17. Knox had an up-and-down rookie season, catching 28 of 50 targets for 388 yards and two touchdowns. On October 24, 2020, Knox was placed on the reserve/COVID-19 list after testing positive for the virus. He was activated on November 5. Knox played in 12 games, starting seven, in 2020, catching 24 passes for 288 yards and three touchdowns. In Buffalo's
Wild Card Round victory over the
Indianapolis Colts, Knox caught two passes for five yards, including a two-yard touchdown from Josh Allen in the first quarter of the Bills' eventual 27–24 victory. In the
AFC Championship against the
Kansas City Chiefs, Knox recorded six catches for 42 yards and a touchdown during the 38–24 loss. Knox became a more prominent part of the Bills' passing attack in 2021. In Week 4, in a 40–0 victory over the
Houston Texans, he had two receiving touchdowns. In Week 5 against the Chiefs, he had three receptions for 117 yards and a touchdown in the 38–20 victory. During
Thanksgiving Day against the
New Orleans Saints, he caught two touchdowns to raise his season total to 7, overtaking Buffalo's franchise record for most receiving touchdowns in a season by a tight end. On September 7, 2022, the Bills signed Knox to a four-year $53.6 million extension, making him one of the top paid tight ends in the league. Knox finished the 2022 season with 48 receptions for 517 receiving yards and six receiving touchdowns. He scored a receiving touchdown in the Bills' 34–31
Wild Card Round victory over the
Miami Dolphins. The Bills drafted tight end
Dalton Kincaid in the first round of the
2023 NFL draft to complement Knox, signaling an intent to use more double tight end formations on offense. On October 26, 2023, Knox was placed on injured reserve after undergoing wrist surgery. He was activated on December 9. He had 22 receptions for 186 yards and two touchdowns in the 2023 season. In the Wild Card Round win against the Steelers, he had a receiving touchdown. In the 2024 season, Knox had 22 receptions for 311 yards and one touchdown. In Week 14 of the 2025 season, Knox led the Bills in receiving in their come-from-behind 39–34 win over the Bengals with 93 yards. The following week, he scored 2 touchdowns to help the Bills overcome a 21–0 deficit and beat the
New England Patriots 35–31, also surpassing
Pete Metzelaars's team record for most career touchdowns by a tight end. He finished the 2025 season with 36 receptions for 417 yards and four touchdowns. On March 10, 2026, Knox re-signed with the Bills on a three-year contract. ==NFL career statistics==