Background: Patients with end-stage renal disease on hemodialysis are affected by psychological stressors, which contribute to poor quality of life and negative clinical outcomes. Stress, anxiety, and depression are highly prevalent in this population. Fordyce's happiness program has been believed to be one of the complementary therapies that could promote psychological wellbeing. The goal of this study was to evaluate the effects of Fordyce's happiness program on the stress, anxiety, and depression in patients with hemodialysis. Materials and Methods: This is a clinical trial. A total of 50 patients undergoing hemodialysis were randomly recruited into the study group (n = 25) and the control group (n = 25). Intervention of Fordyce's happiness program was administrated for 20 minutes during hemodialysis sessions once a week for 6 sessions. For the control group, 3 sessions were held by the researcher's colleague through communication, dialogue, and listening to the patients' problems individually. The data was collected by the Stress, Anxiety and Depression (DASS-21) questionnaire. Results: There was a significant difference in the mean scores of stress, anxiety, and depression in the intervention group before immediately after and one month after intervention (P < 0.05), whereas there was no significant difference in the mean scores of stress, anxiety, and depression before, immediately after, and 1 month after intervention in control group. Conclusions: The obtained results showed that Fordyce Happiness Training Program can reduce the stress, anxiety, and depression in patients treated with hemodialysis