The Itacaiúnas River basin, an important watershed for the mining sector in Brazil, has had 51% of its native forest area deforested in the last forty years. It is in the arc of deforestation of the Amazon. It has protected areas essential to local biodiversity maintenance, in addition to owning ore reserves. Here, we present the first study to assess the mean annual, seasonal, and spatialized hydrological processes, providing results on a detailed scale in the basin, including mining sites. We used five future projections of mean monthly temperature and daily precipitation as input to the MGB hydrological model to simulate how hydrological processes, such as evapotranspiration, water availability, and high flows, may change in the next 30 years. The future decrease in precipitation (−8%) and increase in temperature (10%) may strengthen the monsoon seasonal cycle and lengthen the dry month for evapotranspiration. Furthermore, some parts of the basin expect an increase in the high flows (8.1%) and a decrease in water availability (−93.6%). These results provide subsidies to develop adaptation strategies to ensure the viability of mining operations and safeguard the surrounding environment and communities.