As a true freshman, Henderson appeared in 11 games for the Gators with five starts and made 22 tackles with four interceptions. He became the first freshman in Florida's history to return an interception for a touchdown in back-to-back games after doing so in his first two career games against Michigan and Tennessee.[4] In his sophomore year, his first full season as a starter, Henderson recorded 38 tackles, two sacks and two forced fumbles with two interceptions and a team-high seven passes defended and was named second-team All-Southeastern Conference (SEC) by the league's coaches.[5]
Henderson entered his junior season as a preseason first-team All-SEC selection, third-team preseason All-America, and on the Bednarik Award watchlist.[6] Henderson was also named a second-team midseason All-American by the Associated Press despite missing four games due to injury.[7] Henderson finished his junior season with 33 tackles (three for loss), a sack and 11 passes broken up in nine games and was named first-team All-SEC by the league's coaches and a second-team All-American by the Football Writers Association of America.[8] Following the end of the Gators' regular season, Henderson announced that he would forgo his final year of eligibility to enter the 2020 NFL draft and also skip Florida's bowl game. Henderson finished his collegiate career with 93 tackles, 26 passes broken up and six interceptions in 33 games played.[9]
Henderson was selected by the Jacksonville Jaguars in the first round with the ninth overall pick in the 2020 NFL Draft.[12] On July 16, 2020, Henderson signed his four-year rookie contract, worth a fully guaranteed $20.5 million.[13] Henderson made his NFL debut in the season opener on September 13, 2020, against the Indianapolis Colts, starting and recording five tackles and his first career interception, picking off a pass from Philip Rivers and returning it for 22 yards, and defending three passes, including breaking up a pass on a fourth down late in the fourth quarter to secure a Jaguars' 27–20 win, and was named the Pepsi NFL Rookie of the Week.[14][15]
In Week 10 against the Green Bay Packers, Henderson forced a fumble on wide receiver Davante Adams which was recovered by teammate Myles Jack during the 24–20 loss.[16] He was placed on injured reserve on November 19, 2020, with a groin injury.[17]
In October 2020 during a ribbon cutting ceremony, the training center at Christopher Columbus High School, his alma mater, was dedicated in the Henderson Family name due to his generous contribution to the redesign of the facility.
Carolina Panthers
On September 27, 2021, Henderson was traded to the Carolina Panthers with a 2022 fifth-round pick in exchange for tight end Dan Arnold and a 2022 third-round pick.[18] In the 2021 season, he appeared in 12 games and started seven.[19]
In the 2022 season, Henderson started in ten games and appeared in all 17. He finished with 58 total tackles, two interceptions, six passes defended, and one forced fumble.[20]
Houston Texans
On March 21, 2024, Henderson signed with the Houston Texans.[21] He was released on August 27.[22]
Pittsburgh Steelers
On September 25, 2024, Henderson was signed to the Pittsburgh Steelers practice squad. Later on October 21, 2024, he was signed to the active roster.[23]