Native Americans (Indigenous Americans) have high rates of serious illness in the United States. Informal caregivers are heavily relied on in caring for patients in low-resource settings. The needs of caregivers residing on reservations are sorely underreported. Therefore, our objective was to examine relationships between facilitators (communal mastery, cultural identity, and spirituality) and barriers (depression, anxiety, stress, and burden) with supportive care needs among adult informal caregivers in 1 reservation-based community. A cross-sectional survey was distributed in July and August 2022 as part of a larger multimethod, community-based participatory research study. We used descriptive statistics and linear regression models to examine relationships against the primary outcome, the Supportive Care Needs Assessment Tool for Indigenous People. Overall, 127 participants were included; most were female (n = 92, 72.4%), were between 30 and 49 years (n = 57, 44.9%), and had 6 months or less of caregiving experience (n = 41, 32.5%). Higher depression, anxiety, stress, and burden were significantly associated with higher Supportive Care Needs Assessment Tool for Indigenous People scores. Overall, mental health is a significant barrier that may indicate greater supportive care needs among informal caregivers, although further work is needed to differentiate symptoms and their impact on caregiving from a cultural perspective.