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Sickle cell disease (SCD) is a devastating genetic hematologic disorder affecting approximately 80,000 African Americans. Beyond the well-characterized vaso-occlusive pain crises, patients experience significant psychological morbidity, including kinesiophobia (fear of movement) and depression, which profoundly impact quality of life and functional outcomes. This comprehensive review synthesizes current evidence on the relationship between kinesiophobia and depression in SCD patients, with particular attention to gender differences, underlying pathophysiological mechanisms, and clinical implications for multidisciplinary care. We conducted a systematic examination of the literature on kinesiophobia, depression, and psychosocial factors in SCD, incorporating data from multiple cohort studies totaling 247 adult African American patients. Assessment instruments included the Tampa Scale for Kinesiophobia (TSK), Beck Depression Inventory (BDI), and Center for Epidemiologic Studies Depression Scale-Revised (CESD-r). Kinesiophobia prevalence in SCD patients (mean TSK score = 30.48) was comparable to patients with chronic back pain and fibromyalgia. Significant gender differences emerged, with women demonstrating strong positive correlations between kinesiophobia and depression (BDI r = 0.31, p = 0.045; CESD-r = 0.54, p = 0.009), while no significant relationships were observed in men (BDI r = 0.24, p > 0.05; CESD-r = 0.13, p > 0.05). The relationship appears mediated by psychomotor retardation, somatization, and pain catastrophizing behaviors. Fear of movement represents a clinically significant but underrecognized contributor to depressive symptomatology in women with SCD. These findings highlight the need for gender-specific psychological interventions and integrated care approaches that address both physical and mental health components of this complex genetic disorder.