The current era of globalization has seen a pandemic rise in the number of patients with chronic diseases including end-stage renal disease (ESRD). This led to the study of various factors that affect patients’ health-related quality of life (HRQoL). One of the factors that is getting attention lately is the role of religious coping strategies and how it affects the quality of life of patients with chronic patients. Therefore, the present study examined the role of religious coping strategies (RCS) as a mediator between depression and HRQoL of ESRD patients. It was a cross sectional study, involved 274 ESRD patients who is undergoing dialysis treatment at dialysis centre in the Selangor, Kuala Lumpur and Johor. Instruments used were the Short Form-36 (SF-36), Beck Depression Inventory II (BDI II), and Religious Coping Strategies (RCS). Results showed that there were significant correlations between depression and RCS with HRQoL (Physical component summary PCS] and Mental Component Summary MCS]). Meanwhile, religious coping was a partial mediator between depression with PCS and MCS. The results of this study will facilitate health practitioners in developing appropriate interventions that take into account the role of religion to improve patient quality of life towards a more positive and effective manner.