Coronavirus Disease 2019 (COVID-19) is the most devastating pandemic of this century. Little is known about the impact of COVID-19 on children, especially those with underlying conditions. We describe the case of a 4-year-old with hereditary spherocytosis who was found to be positive for COVID-19 and secondary hemolytic anemia. With supportive care and transfusions, he clinically improved, and his hemoglobin stabilized. This case reminds us to remain vigilant in evaluating high risk patients for hemolysis in the face of infection. Further studies on the clinical presentation and trajectory of patients presenting with COVID-19 and underlying disease should be encouraged.