Sickle cell disease (SCD) is the most frequent life-threatening genetic hemoglobinopathy in the world and occurs due to the synthesis of abnormal hemoglobin S (HbS). hemoglobin S-containing red blood cells (RBC) are fragile, leading to hemolysis and anemia, and adhere to the endothelium, leading to hemorheological and hemodynamical disturbances. In its deoxygenated form, HbS may polymerize, leading to sickling of red blood cells and potentially to vasoocclusive crises. Recent findings observed that SCD patients demonstrate significant skeletal muscle remodeling and display reduced muscle functional capacities, contributing to exercise intolerance and poor quality of life. Although acute high-intensity exercise is not recommended for SCD patients because it may increase the risk of sickling, regular moderate-intensity physical activity could have beneficial effects on skeletal muscle and more generally on the well-being of SCD patients. This article reviews the literature regarding the impact of the disease on muscular tissue characteristics and function, as well as the corresponding implications for SCD patients' quality of life.