Hamlin was selected by the Buffalo Bills in the sixth round of the 2021 NFL draft and played a reserve role in his first season.

Hamlin became a starter following a season-ending injury to Micah Hyde and recorded 91 tackles and 1.5 sacks.

Hamlin suffered a cardiac arrest during a Monday Night Football game against the Cincinnati Bengals and was hospitalized in critical condition.

Hamlin was released from the hospital nine days later and eventually returned to professional football, playing in the preseason and regular season games.

Hamlin started at safety in the Bills' week one game against the Arizona Cardinals, marking his first start since his cardiac arrest.

Hamlin recorded his first career interception in a 47–10 Bills win over the Jacksonville Jaguars.