Introduction: Renal failure is the irreversible degeneration of renal function, which is typically treated by hemodialysis. Hemodialysis causes mental stresses, fatigue, and depression in affected patients. The purpose of this study was to determine the effect of laughter therapy on fatigue and depression in hemodialysis patients. Materials and Methods: This clinical trial study was carried out based on total count sampling on 70 hemodialysis patients in the cities of Sowmehsara and Fouman in 2017. The Demographic Questionnaire, Multidimensional Fatigue Questionnaire, and Beck Depression Inventory-II (BDI-II) were completed by both groups before the intervention. Afterward, 8 laughter therapy sessions each lasting 30-45 minutes were held for four weeks for the participants in the intervention group. At the end of the last session, the questionnaires were again completed by the participants in both groups. During the intervention, the control group received only usual treatments. The collected data were analyzed using independent samples t-test, Loon test, non-parametric Mann-Whitney U test, and Wilcoxon rank-sum test. Results: The mean scores of depression and fatigue in the two groups were not significant before the intervention (p>0. 5). However, after the intervention, depression and fatigue scores showed significant differences between the two groups (p=0. 001). The depression score in the treatment group decreased from 24. 73± 11. 56 to 10. 88± 5. 00 and the fatigue score decreased from 74. 95± 16. 07 to 52. 53± 14. 70. Conclusion: According to the findings, laughter therapy reduced depression and fatigue in patients undergoing hemodialysis. Therefore, senior nursing managers are recommended to take required actions to apply laughter therapy to improve the quality of life of hemodialysis patients.