This study examined the relationship between stress and depression, and the mediating role of spiritual factors among 316 older adults, 65 years or older in assisted living facilities (ALFs). Hierarchical regression analysis revealed that a high level of stress was associated with a high level of depression among older residents. For male residents, a Sobel test indicated that the direct coefficient of stress on depression decreased when spiritual coping and forgiveness were mediated. However, there was no significant mediating role of spiritual factors for stress and depression among female residents. This study suggests the importance of providing spiritual support for older men who are dealing with significant stress as a way to minimize depressive symptoms.