While packed red blood cell (PRBC) transfusion therapy is a mainstay in the treatment of certain patients with sickle cell disease (SCD) and the standard of care for preoperative management, there are associated risks. Delayed hemolytic transfusion reaction (DHTR) is a risk of PRBC transfusion occurring 2 to 20 days from transfusion and typically presents with severe pain characteristic of vaso-occlusive crisis, fever, and hemolytic anemia. DHTRs are uncommon, occurring in only 4% to 11% of transfused patients with SCD, but may be catastrophic in nature with progression to multiorgan failure within hours. Here, we describe a case of a 20-year-old female with sickle cell SS disease who developed a severe DHTR 5 days following an elective preoperative PRBC transfusion, and rapidly progressed to multiorgan failure and death. This is the first reported case of a catastrophic DHTR in a patient with SCD without any detectable known or new alloantibodies.