Fournier's gangrene is a potentially fatal emergency condition characterized by necrotizing fasciitis and supported by an infection of the external genital, perineal and perianal region, with a rapid and progressive spread from subcutaneous fat tissue to fascial planes. In this case report, a 52-year-old man, with a history of hepatitis C-virus (HCV)-related chronic liver disease and cocaine use disorder for which he was receiving methadone maintenance therapy, was admitted to the Emergency Department with necrotic tissue involving the external genitalia. Fournier's gangrene is usually due to compromised host immunity, without a precise cause of bacterial infection; here it is linked to a loco-regional intravenous injection of cocaine. A multimodal approach, including a wide surgical debridement and a postponed skin graft, was needed. Here we report this case, with a narrative review of the literature.