End-stage renal disease (ESRD) introduces physical, psychological, social, emotional, and spiritual challenges into patients' lives. Spirituality has been found to contribute to improved health outcomes, mainly in the areas of quality of life (QoL) and well-being in especially in terminal, life-threatening, and chronic diseases. The current study was planned to assess the effect of Spiritual therapy in patient undergoing hemodialysis (HD). Post approval from Ethics Committee, the study was commenced at Dialysis Center, Bhaktivedanta Hospital and Research Institute and conducted for 12 weeks. Participants were divided into two groups (one with spiritual intervention and other being control). Spiritual chanting and listening to it was the intervention. The outcome was assessed by kidney diseases QoL (KDQoL), spiritual well-being [Functional assessment of chronic illness therapy (FACIT) Sp 12] score, certain components of ESRD targeted area, 36 item health survey, and laboratory and nutritional parameters. Statistical analysis was done using IBM SPSS Statistics version 20.0 at 5% significance. A total of 100 participants were included in study; males were outnumbered. KDQoL, ESRD targeted areas, components of 36-item health survey, and FACIT Sp 12 scores were significantly different on better side in interventional group at six weeks and 12 weeks. There was no significant difference in laboratory and nutritional parameters. The findings from this study contribute knowledge to increase our understanding of the influence of spirituality on the health outcomes and general well-being of patients with ESRD currently receiving HD treatment. The current study adds to the evidence in support of the use of spiritual therapy in chronic kidney disease patients on HD.