Purpose: To examine a predictive theoretical model of psychological distress based on the following variables reflected on family caregivers of patients with cancer: the unmet supportive care needs, subjective caregiving burden, social support, and the positive aspects of caregiving. Methods: A cross-sectional descriptive study was conducted on a sample of 484 dyads of patients and their family caregivers. The caregivers completed structured questionnaires designed to measure psychological distress, unmet supportive care needs, subjective caregiving burden, positive aspects of caregiving, and social support. Patients' demographic variables and medical data were collected from a medical record review. We used a structural equation modeling to test the predictive theoretical model. Results: Path analysis results partially supported the proposed model with satisfactory fit indices. Specifically, family caregivers with an increasing number of unmet needs or a heavier caregiving burden were more likely to have more severe psychological distress. Bootstrapping results supported that the caregiving burden and social support were significant mediators. Greater unmet supportive care needs predicted higher psychological distress through increasing caregiving burden. Stronger social support predicted lower psychological distress through decreasing caregiving burden. Positive aspects of caregiving predicted lower caregiving burden through the increasing perceived social support, which in turn eliminated psychological distress. Conclusions: Unmet supportive care needs could cause psychological distress through increasing caregiving burden. The positive aspects of caregiving reduced caregiving burden through increasing social support, which subsequently alleviated psychological distress. Interventions that aim to satisfy supportive care needs, to reduce caregiving burden, and to strengthen social support ties may boost the mental health of family caregivers.