Melifonwu committed to Syracuse University to play college football.
[10] Melifonwu signed his four-year rookie contract with Detroit on July 23, 2021.
[11] On September 22, 2021, Melifonwu was placed on injured reserve after suffering a thigh injury in Week 2.
On June 1, 2022, Melifonwu started snaps as both a cornerback and a safety.
[13] On December 24, 2023, Melifonwu intercepted a pass from Minnesota Vikings quarterback Nick Mullens to end the game, clinching the Lions' first division title since 1993, and the first NFC North title for the Lions.