Background <p>First Nations children in Canada experience lower vaccination coverage compared to the general population, yet research on vaccination confidence, access, and uptake in on-reserve communities remains limited. This study examines barriers to childhood vaccination and the role of the Early Years (EY) home visiting program in influencing uptake in Maskwacis, a First Nations Community in central Alberta.</p> Methods <p>Guided by community-based participatory research, data were collected with parents, through interviews (<i>n</i> = 23); EY home visitors who provide support to parents, through a review of case notes (<i>n</i> = 851 entries), a survey (<i>n</i> = 7), and focus groups (<i>n</i> = 3 with 18 participants); and health staff who administer vaccinations, through a survey (<i>n</i> = 5) and interviews (<i>n</i> = 4). Data were analyzed using qualitative content analysis.</p> Results <p>Participants identified multiple barriers to vaccination, including resource challenges preventing them from accessing appointments, limited information and misinformation about vaccinations, sociocultural concerns, fear of injections, negative healthcare experiences, and pandemic-related challenges. These barriers were often rooted in a distrust of healthcare systems and a strong desire amongst parents to protect their children. The EY program facilitated vaccination by providing parents with accurate information, assisting families with attending appointments, and fostering trusting relationships with parents. Central to these facilitators was reassurance parents received that vaccines are safe and important for their children’s health.</p> Conclusions <p>The study offers key insights into barriers to childhood vaccination in an on-reserve First Nations community and the role of culturally grounded home visiting programs in facilitating confidence and access. The findings can inform strategies to strengthen vaccination uptake among First Nations children and families and advance health equity.</p>