Sickle cell disease (SCD) is a chronic inflammatory condition characterized by hemoglobin polymerization that precipitates recurrent vaso-occlusion, endothelial dysfunction, and multi-organ damage. Menstruation in persons with SCD presents a unique challenge due to blood loss and its ability to exacerbate SCD pain. This interaction between SCD-related vascular stress and menstruation-induced inflammation amplifies the risk of acute pain episodes during menstruation. In this manuscript, we explore the intersection of SCD and menstruation, emphasizing the role of hormonal therapy in managing menstruation-associated acute SCD pain. Progestin-only therapies, such as depot medroxyprogesterone acetate (DMPA) and levonorgestrel intrauterine devices (LNG-IUDs), are particularly effective in reducing menstrual blood loss. Data suggests DMPA mitigates acute SCD pain episodes around menstruation with minimal thrombotic risk in persons with SCD. Despite their effectiveness in menstrual regulation, combined hormonal contraceptives (CHCs) pose a significant concern due to their potential to exacerbate the hypercoagulable state in individuals with SCD. We highlight the importance of comprehensive care and collaboration between gynecologists and hematologists to optimize the management of menstruation-associated SCD pain.