Simmons redshirted his first year at Clemson in 2016. As a safety in 2017, he played in 14 games, recording 49 tackles and one sack.[4] In 2018, he converted to linebacker.[5] In 15 games, Simmons had 97 tackles, 1.5 sacks and one interception.[6][7] He returned to Clemson in 2019 rather than enter the 2019 NFL draft.[8] Simmons received the Butkus Award as the nation's best linebacker for his performance that year.[9] After graduating in December 2019 with a degree in sports communication, Simmons announced that he would forgo his senior year by declaring for the 2020 NFL draft.[10][11] During his time at Clemson, Simmons was noted for his positional versatility, taking snaps at linebacker, defensive end, cornerback, and safety.[12][13]
Simmons participated in the 2020 NFL Combine, leading all linebackers with a 4.39-second 40-yard dash.[17] He was one of 58 players invited to the 2020 NFL Draft, which was held virtually due to social distancing regulations arising from the COVID-19 pandemic, where he was selected by the Arizona Cardinals with the eighth overall pick.[18][19]
Despite playing only five snaps in Week 7 against the Seattle Seahawks on Sunday Night Football, Simmons recorded his first career interception off Russell Wilson with a minute left in overtime, helping the Cardinals win 37–34.[20]
Simmons entered the 2021 season as a starting inside linebacker. He started all 17 games, finishing third on the team with 105 tackles, 1.5 sacks, four forced fumbles, and seven passes defensed.
In Week 7 against the New Orleans Saints, Simmons recorded five tackles and returned an interception 56 yards for his first NFL touchdown in the second quarter in the 42–34 win.[21]
On May 1, 2023, the Cardinals declined the fifth-year option of Simmons' contract, making him a free agent in the 2024 offseason.[22]
During a Week 11 game against the Washington Commanders, Simmons intercepted a pass off of Sam Howell and returned it for a touchdown, sealing the game and resulting in a victory for the Giants.[25]
On April 5, 2024 the Giants re-signed Simmons to a 1 year, $2,000,000 deal.[26]