Sickle cell disease is a common inherited blood disorder that is characterized by the presence of sickle-shaped red blood cells. The clinical manifestations of sickle cell disease vary, but they may be attributed to three mechanisms: vaso-occlusion, chronic hemolytic anemia, and infection. The imaging appearances of central nervous system and musculoskeletal involvement by sickle cell disease have been well documented; however, involvement in the head and neck often is underappreciated, although it is not uncommon. In the head and neck, sickle cell disease can involve the inner ears, orbits, paranasal sinuses, bones, lymph nodes, and vessels. Manifestations of inner ear involvement include labyrinthine hemorrhage and labyrinthitis ossificans. In the orbits, they include lacrimal gland swelling, orbital wall infarction, and subperiosteal hemorrhage or fluid. In the paranasal sinuses, extramedullary hematopoiesis is seen. When bone is involved, infarction, osteomyelitis, bone marrow hyperplasia, and deposition of iron in bone marrow are seen in the maxillofacial bone and skull base. When lymph nodes are involved, lymphadenopathy is seen, and when blood vessels are involved, arterial stenosis and ectasia are seen. An understanding of the pathophysiology of sickle cell disease and knowledge of the various clinical and radiologic manifestations are crucial for prompt diagnosis and appropriate treatment.