When the treatment process of cancer patients changes to outpatient treatment, the burden on family members increases and they often experience burnout. Burnout not only effects the family members themselves but may also have a negative effect on the health of the cancer patient. Therefore, healthcare providers should evaluate burnout in the family members of cancer patients and actively make efforts towards their burnout management. This study investigated the mediating effect of depression on the relationship between social support, spirituality, and burnout in family members of patients with cancer. Participants were 151 family members of patients with cancer who were receiving chemotherapy as outpatients at a single university hospital in Korea. Data was collected from 2 March to 31 May 2016, using self-reported questionnaires. Collected data was analyzed with t-tests, analysis of variance (ANOVA), Pearson’s correlations, Baron and Kenny’s three-step regression method, and the Sobel test. The participants’ mean burnout was below the median. The participants’ depression partially mediated the relationship of both social support and spirituality on burnout. Strategies to assess depression and strengthen social support and spirituality should be developed to manage burnout in family members’.