Potassium dynamics are critical in the pathophysiology of sickle cell anemia (SCA), a genetic disorder characterized by the presence of abnormally shaped red blood cells that lead to various complications such as vaso-occlusive crises and hemolytic anemia. This review focuses on the clinical implications and pathophysiological insights of potassium regulation in SCA, highlighting its impact on disease progression and potential therapeutic strategies. The dysregulation of potassium transport in SCA leads to significant K+ efflux and cellular dehydration, exacerbating the sickling process. Dehydrated sickle cells, due to potassium loss, become more rigid and prone to causing blockages in small blood vessels, leading to painful vaso-occlusive crises and ischemia. Furthermore, chronic hemolysis in SCA, aggravated by potassium imbalance, contributes to severe anemia and systemic complications. These insights underscore the importance of maintaining potassium homeostasis to mitigate disease severity and improve patient outcomes. Therapeutic strategies targeting potassium regulation show promise in managing SCA. Inhibitors of the Gardos channel, such as senicapoc, have demonstrated potential in reducing sickling and hemolysis. Additionally, hydration therapy plays a crucial role in maintaining electrolyte balance and preventing RBC dehydration. A comprehensive approach that includes monitoring and correcting electrolyte imbalances, along with standard treatments like hydroxyurea and blood transfusions, is essential for effective disease management.