Background: A common problem in hemodialysis patients, fatigue is a personal perception of extreme tiredness that impairs their quality of life, physical and mental abilities, activity levels, and performance. Study objective(s): This comprehensive study aims to assess the impact of fatigue on health-related quality of life in hemodialysis patients. Methodology: A descriptive A-non-probability (purposive sample) of (205) male and female hemodialysis patients in AL-Diwaniyah City with end-stage renal disease and undergoing hemodialysis. Most patients were diagnosed with ESRD > one year ago, including those who have been on a maintenance hemodialysis programmer for more than a year. A validated and comprehensive health-related quality of life questionnaire (SF-36) tailored for individuals undergoing hemodialysis was utilized to assess fatigue and health-related quality of life among hepatitis and non-hepatitis patients undergoing hemodialysis. The study was conducted at hemodialysis centers, ensuring representation from different geographic regions and patient populations. Result: A total of 205 hemodialysis patients participated in the study. The results revealed that most participants had moderate fatigue (88 (42.9%), mild fatigue (61 (29.8%), and severe fatigue (56 (27.3%). The patient's overall health-related quality of life was found to be low, with a mean score of 19.82. conclusion: Fatigue is a prevalent symptom in hemodialysis patients, affecting their ability to engage in routine activities and self-care, negatively impacting self-confidence and health-related quality of life. Addressing fatigue is crucial for improving physical well-being and mental health.