Background: Despite historical and contemporary trauma, American Indian and Alaska Native (AIAN; Indigenous) communities responded with resilience to the COVID-19 pandemic. However, AIANs experienced disproportionate rates of infection, hospitalization, death, and reduced life expectancy. School closures exacerbated disparities, leading to learning loss, economic instability, and mental health challenges among AIAN youth. Methods: The Project SafeSchools cohort study employed a comprehensive longitudinal convergent mixed-methods approach, integrating community-based participatory research principles. The study enrolled Navajo Nation caregivers whose children were eligible to attend local reservation-based schools. We conducted an analysis of caregiver self-report baseline data collected between August 2021 and May 2022. Results: A total of 242 caregivers completed at least part of the baseline assessment and were included in data analysis. Caregivers were primarily female (88.7%), non-Hispanic (97%), and Indigenous (97%). Most caregivers were in their late 30s (mean age 38), with varying educational backgrounds and employment statuses. Children were evenly split between males and females and distributed across different age groups. Most children attended school at baseline in various formats, including in-person, hybrid, and online-only settings. Caregivers reported a range of psychosocial and behavioral risks, including general mental distress, depressive symptoms, and anxiety for themselves and their children. Furthermore, caregivers and children exhibited various protective factors, such as strong cultural identity, resilience, and academic self-efficacy. Conclusions: This study highlights the higher rates of mental health distress among participating caregivers and children compared to national averages. Despite these challenges, cultural protective factors remained strong and should guide future crisis response efforts.