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One of the important issues regarding caring for patients with mental disorders is the high prevalence of stress, anxiety, and depression in their caregivers. This study aimed to investigate the effect of a spirituality-based program on stress, anxiety, and depression of caregivers of patients with mental disorders. This clinical-trial study involved 60 family caregivers of patients with mental disorders who were referred to the clinic of Shahid Ayatollah Modarres Psychiatric Hospital in Isfahan, Iran, during 2019-2020. Accordingly, the samples were selected using convenient sampling method and then divided into two groups of experimental and control by simple random allocation. Next, the spirituality-based intervention was performed for the intervention group, and the needed data were collected in both intervention and control groups before, immediately after, and one month after the intervention. The data collection tool used in this study was DASS-21 questionnaire. No significant differences were observed between the two groups in terms of the mean scores of stress, anxiety, and depression (p > 0.05) before the intervention. However, some significant differences were found in terms of the stress, anxiety, and depression scores between the two groups immediately (p < 0.001) and one month after the intervention (p < 0.001). The spirituality-based program seemed to affect stress, anxiety, and depression of caregivers of patients with mental disorders positively. So, it is suggested to perform this intervention as an inexpensive and available supportive method for family caregivers of patients with mental disorders., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)