Alloimmunization has been reported in patients with sickle cell disease (SCD). Delayed hemolytic transfusion reaction (DHTR) is one of the complications of alloimmunization. DHTR is of particular clinical significance in this patient population as it may pose a diagnostic and management challenge to most healthcare providers. Symptoms of DHTR are often misinterpreted as pain crisis or worsening of baseline anemia. Furthermore, DHTR may take a turn for the worse in patients with SCD, thereby leading to worsening anemia and hyper-hemolytic crisis. In this report, we discuss the case of a 33-year-old African female, with hemoglobin SS (Hb SS) SCD and a history of multiple blood transfusions in her home country of Nigeria, who presented to the emergency department with generalized body pain, which was typical of her prior vaso-occlusive crisis (VOC). The trigger of her crisis was an acute onset of sepsis secondary to Escherichia coli (E. coli)-associated pyelonephritis. Owing to a worsening of her VOC and a significant drop in her steady-state Hb levels, she required a blood transfusion of one unit of packed red blood cells (PRBC), which was later complicated by a delayed hemolytic reaction and worsening anemia.