Leon S. Kennedy returns as a fully playable protagonist, depicted as a 51-year-old, "hot uncle" figure with a gravelly voice, sporting a black fur-collared jacket and tactical gear. Set in 2028, he assists FBI agent Grace Ashcroft, wielding high-level combat skills similar to the end of RE4, including chainsaw usage.

28 years following the Raccoon City outbreak, the DSO decided to initiate an investigation into a mysterious case of unidentifiable deadly illness that affected any survivors.