The Amazonian indigenous peoples depend on natural resources to live, but human activities’ growing impacts threaten their health and livelihoods. Our objectives were to present the principal results of an integrated and multidisciplinary analysis of the health parameters and assess the mercury (Hg) exposure levels in indigenous populations in the Brazilian Amazon. We carried out a cross-sectional study based on a census of three Munduruku indigenous villages (Sawré Muybu, Poxo Muybu, and Sawré Aboy), located in the Sawré Muybu Indigenous Land, between 29 October and 9 November 2019. The investigation included: (i) sociodemographic characterization of the participants; (ii) health assessment; (iii) genetic polymorphism analysis; (iv) hair mercury determination; and (v) fish mercury determination. We used the logistic regression model with conditional Prevalence Ratio (PR), with the respective 95% confidence intervals (CI95%) to explore factors associated with mercury exposure levels ≥6.0 µg/g. A total of 200 participants were interviewed. Mercury levels (197 hair samples) ranged from 1.4 to 23.9 µg/g, with significant differences between the villages (Kruskal–Wallis test: 19.9; p-value < 0.001). On average, the general prevalence of Hg exposure ≥ 6.0 µg/g was 57.9%. For participants ≥12 years old, the Hg exposure ≥6.0 µg/g showed associated with no regular income (PR: 1.3; CI95%: 1.0–1.8), high blood pressure (PR: 1.6; CI95%: 1.3–2.1) and was more prominent in Sawré Aboy village (PR: 1.8; CI95%: 1.3–2.3). For women of childbearing age, the Hg exposure ≥6.0 µg/g was associated with high blood pressure (PR: 1.9; CI95%: 1.2–2.3), with pregnancy (PR: 1.5; CI95%: 1.0–2.1) and was more prominent among residents in Poxo Muybu (PR: 1.9; CI95%: 1.0–3.4) and Sawré Aboy (PR: 2.5; CI95%: 1.4–4.4) villages. Our f indings suggest that chronic mercury exposure causes harmful effects to the studied indigenous communities, especially considering vulnerable groups of the population, such as women of childbearing age. Lastly, we propose to stop the illegal mining in these areas and develop a risk management plan that aims to ensure the health, livelihoods, and human rights of the indigenous people from AmazonBasin.