Ceftriaxone is an empiric antibiotic widely used in children and is likely to cause ceftriaxone-induced immune hemolytic anemia (CIIHA). This adverse reaction to ceftriaxone may result in fatal and severe complications if not diagnosed early. Herein, we describe management of a rare case of CIIHA. A 5-year-old boy, with sickle cell disease (SCD), presented with signs of vaso-occlusive crises (VOC), osteomyelitis (OM), in form of; shoulder pain, swelling and fever treated with ceftriaxone infusion. Post-infusion patient experienced severe pale, tachycardia, rapid breathing and lethargic with dark color of urine. Lab investigations confirmed a sudden drop in hemoglobin indicated severe anemia, hemolysis and thrombocytopenia. Immediately, the ceftriaxone infusion was stopped, and supportive care was given.