Non-communicable chronic diseases (NCDs) are the most widespread cause of mortality worldwide. Intestinal microbiota balance can be altered by changes in the abundance and/or diversity of intestinal microbiota, indicating a role of intestinal microbiota in NCD development. This review discusses the findings of in vitro studies, pre-clinical studies and clinical trials on the effects of Brazilian native fruits, their by-products, as well as their bioactive compounds on human intestinal microbiota and NCD. The major bioactive compounds in Brazilian native fruits and their by-products, and the impacts of their administration on outcomes linked to intestinal microbiota modulation are discussed. Mechanisms of intestinal microbiota affecting NCD could be linked to the modulation of absorption and energy balance, immune and endocrine systems, and inflammatory response. Brazilian native fruits, such as acerola, açaí, baru, buriti, guava, jabuticaba, juçara, and passion fruit, have several bioactive compounds, soluble and insoluble fibers, and a variety of phenolic compounds, which are capable of changing these key mechanisms. Brazilian native fruits and their by-products can help to promote positive intestinal and systemic health benefits by driving alterations in the composition of the human intestinal microbiota, and increasing the production of distinct short-chain fatty acids and phenolic metabolites, thereby enhancing intestinal integrity and homeostasis. Evidence from available literature shows that the modulatory impacts of Brazilian native fruits and their by-products on the composition and metabolic activity of the intestinal microbiota could improve several clinical repercussions associated with NCD, reinforcing the influence of intestinal microbiota in extra-intestinal outcomes.