<p>This Review describes the burden of cardiovascular disease across Indigenous populations and contextualizes the potential drivers and contributors to inequalities between Indigenous and non-Indigenous populations. The focus is on Indigenous populations across Aotearoa New Zealand, Australia, Canada and the USA, including Aboriginal and Torres Strait Islander, American Indian, Alaska Native, Canadian First Nations, Inuit, Métis, Māori, Native Hawaiian and Pacific Islander peoples. Available data show that cardiovascular disease is a leading cause of premature and excess disease burden for Indigenous populations, characterized by excess mortality, morbidity and related health-care utilization. Inequities emerge early in the life course, in adolescence and young adulthood. However, the availability of data from Indigenous populations in each country is severely limited, highlighting the need for comprehensive research and collection of administrative data to enable surveillance, monitor secular trends in inequality, and identify targets for policy and health-system reform. This Review posits the complex interplay between determinants of cardiovascular disease, incorporating intergenerational socioeconomic disadvantage, structural discrimination and racism, and the way in which colonization increases exposure to risks, contributing to the erosion of cultural strengths and cardioprotective factors. These determinants represent key targets for preventative and promotive action to improve and sustain the cardiovascular wellbeing of Indigenous populations.</p>