The COVID-19 pandemic has disproportionately impacted Indigenous populations worldwide placing much importance on rapid and equitable vaccination. Nevertheless, many Indigenous communities have reported high vaccine hesitancy and low COVID-19 vaccine uptake. This may be attributed to various factors, including a lack of support for Indigenous leadership efforts to protect their communities and the pervasive infodemic targeting First Nations Peoples. In August 2022, we hosted an international symposium to bring together Indigenous and non-Indigenous community leaders, clinicians, and researchers to discuss pandemic experiences and lessons learnt. This commentary highlights examples of harnessing Indigenous leadership and self-governance to design and deliver tailored community-based and culturally appropriate COVID-19 vaccination programmes that improved vaccine uptake in Australia and Canada. These case studies demonstrate that Indigenous social-governance systems need to be valued, respected, and upheld if we are to make meaningful efforts to address health inequities among Indigenous communities during future pandemics.