COVID-19 disease causes primarily pulmonary manifestations, with myriad other clinical manifestations especially in high-risk conditions, including sickle cell disease (SCD). We present a 19-year-old with SCD on deferasirox with COVID-19 infection involving pain and acute chest syndrome, four weeks later developing hyperammonemia and hyperinflammatory multiorgan failure. Successful treatment included hemodialysis, red cell exchange transfusion, and therapeutic plasma exchange. Though SCD-related multiorgan failure and deferasirox-related hyperammonemia are reported, this case suggests multifactorial etiology including COVID-19-related hyperinflammation. Awareness of potential hepatic and systemic complications, and consideration for exchange transfusion and therapeutic plasma exchange, may reduce severity of COVID-19 sequelae in SCD.