Objectives: Patients undergoing hemodialysis encounter a wide range of complex challenges, underscoring the essential role of self-care in disease management. The present study aimed to examine the effectiveness of an educational intervention grounded in Orem’s self-care model for enhancing treatment adherence, self-care behaviors, and quality of life among hemodialysis patients in southern Iran. Methods: This single-blind randomized controlled trial included 120 hemodialysis patients who met the predetermined eligibility criteria. Data were collected between April 2023 and August 2023 at 2 university-affiliated teaching hospitals located in southern Iran. After providing informed consent, participants were randomly allocated to either the intervention group (n=60) or the control group (n=60) through a simple randomization procedure. Three psychometrically robust instruments were used to collect data: the End-Stage Renal Disease Adherence Questionnaire, the Kidney Disease Quality of Life Short Form, and the Self-Management Behavior Scale. Statistical analyses were performed using SPSS version 23, and p-values<0.05 were considered statistically significant. Results: At baseline, no statistically significant differences were observed between the intervention and control groups in the mean scores of the measured variables. However, immediately following the intervention and at the 3-month follow-up, the intervention group demonstrated statistically significant improvements across all 3 variables. Conclusions The findings underscore the effectiveness of an educational program based on Orem’s self-care model in significantly improving self-care behaviors, treatment adherence, and quality of life among hemodialysis patients.