Background: Hemodialysis impacts the quality of life of patients with end-stage renal disease. Particularly, depression is the most common psychological condition among patients. Self-care self-efficacy might play an important role in quality of life of patients with hemodialysis.Objective: This study was designed to explore the relationships among self-care self-efficacy, depression, and quality of life. The second aim was to explore the extent to which self-care self-efficacy and depression explain the variance in quality of life of patients on hemodialysis.Methods: This cross-sectional study included 127 patients receiving hemodialysis and used the Short Form 36 Health Survey, the Strategies Used by People to Promote Health, and the Patient Health Questionnaire 9 to evaluate quality of life, self-care self-efficacy, and depression. Data was analyzed using independent t-test, analysis of variance, Pearson’s correlation and hierarchical multiple regression.Results: The findings indicated that self-care self-efficacy was significantly positively correlated (PCSr= .533,p < 0.001, MCSr= .47,p < .001) and depression was significantly negatively correlated (PCSr= −.446,p < .001, MCSr= −.605,p < .001) with the two quality of life components. Self-care self-efficacy and depression were significant predictors of the physical (R2inc= 0.09,β= -0.38,p<0.001,R2inc= 0.12,β =-0.22,p<0.001) and mental (R2inc= 0.04%,β= -0.25,p<0.001,R2inc= 0.33,β= -0.51,p<0.001) quality of life of hemodialysis patients.Conclusions: Health professionals may target improving self-care self-efficacy and reducing depressive symptoms to enhance patient quality of life.