The goals with treatment are to relieve pain, minimize complications and organ damage, and prevent infection. Newborns with sickle cell disease are often placed on long-term penicillin therapy to prevent pneumonia and other infections. Children and adults may be treated with hydroxyurea, a medication that has been found to reduce the number of crises and lessen the severity of those that do occur. The number of crises can also be minimized by avoiding situations that frequently trigger episodes, such as overexertion, dehydration, temperature extremes, changes in altitude, smoking, and stress.

Stroke, aplastic crises, acute chest syndrome, swollen spleens, and occasionally severe crises may need to be treated with blood transfusions or exchange transfusions to raise the red blood cell count and reduce the number of sickle cells. Some patients who have had multiple transfusions may require treatment to address iron overload. Patients with organ damage and/or organ failure may require additional treatments, such as having their spleen removed.