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A recent surge of Coronavirus disease 2019 (COVID-19) cases in First Nations communities during the second wave of the pandemic has raised concerns over the susceptibility of First Nations communities to COVID-19, as well as the preparedness of Canada’s healthcare system in supporting isolated First Nations communities during the pandemic. Despite government initiatives and funding throughout the pandemic, it is well established that First Nations communities continue to face longstanding health disparities when compared to the rest of the Canadian population. In this commentary, we argue for a multidimensional approach that encompasses the social determinants of health for understanding the susceptibility of First Nations to COVID-19 outbreaks, and potential solutions aimed at primary prevention and community preparedness that will benefit First Nations communities across Canada. Based on this approach, we recommend that healthcare providers and community members advocate at both provincial and federal levels for proper housing, access to clean water, implementation of culturally competent care into practice, adequate health teaching and understanding of public health recommendations (e.g. proper handwashing techniques) and robust monitoring of patients who may be at risk for COVID-19 infection.