Drug-induced immune hemolytic anemia (DIIHA) is commonly attributed to cephalosporins. Ceftriaxone is the most frequently administered cephalosporin in patients with sickle cell disease. We present a pediatric patient with severe DIIHA (hemoglobin < 2 g/dl) who survived. Since DIIHA often goes undiagnosed until late in the course, vigilance of DIIHA minimizes unnecessary diagnostic tests and therapies. DIIHA likely remains under-recognized in all patient subpopulations due to its rarity and overlapping presentations with other conditions. Distinction between exacerbation of chronic hemolysis and new onset of acute hemolysis poses a unique challenge in patients with sickle cell disease. A thorough analysis is warranted to better identify factors within the pediatric sickle cell population that may increase the predisposition for DIIHA, particularly due to ceftriaxone.