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Objectives: The First Nations people experience significant challenges that may influence the ability to follow COVID-19 public health directives on-reserve. This study aimed to describe experiences, perceptions and circumstances of an Alberta First Nations community, related to COVID-19 public health advice. We hypothesized that many challenges ensued when following and implementing advice from public health experts., Methods: With First Nations leadership and staff, an online cross-sectional survey was deployed between April 24 and June 25, 2020. It assessed the appropriateness of public health advice to curb COVID-19 within this large First Nations community. Both quantitative and qualitative data were captured and described., Results: A total of 106 adults living on-reserve responded; over 80% were female. Difficulty accessing food was significant by employment status (p = 0.0004). Those people with lower income found accessing food (p = 0.0190) and getting essential medical care (p = 0.0060), clothing (p = 0.0280) and transportation (p = 0.0027) more difficult. Some respondents described lost income associated with COVID-19 experiences, as well as difficulties accessing essential supplies. Respondents found "proper handwashing" most easy (98%) and "keeping a distance of 2 m from others" most difficult (23%). Many respondents found following public health advice within their personal domain easy and put "family safety" first but experienced some difficulties when navigating social aspects and obligations, particularly when unable to control the actions of others. People stated wanting clear information, but were sometimes critical of the COVID-19 response., Conclusion: First Nations people face many additional challenges within the COVID-19 response, driven in part by ongoing issues related to significant societal, economic, and systemic factors., (© 2021. The Author(s), under exclusive licence to The Author(s) under exclusive license to The Canadian Public Health Association.)