Despite the overall extension of the Amazon Basin (approximately 6,000,000 km2),which encompasses such a complex ecosystem and territories belonging to seven different nations, it is worth mentioning that environmental assessments related to changes in land use and land cover (LULC) in this region are often conducted respecting geopolitical boundaries associated with each country or taking into account the so-called Amazon biome. With the purpose of prospecting the intricate and hidden hydrological patterns, we undertake an in-depth evaluation of the water balance along the 2001–2021 time span across the whole basin, whose behavior depends on the features deriving from the metamorphoses in land use and land cover. To accomplish that task, the influence of the components of the water balance, namely rainfall and evapotranspiration, jointly with the terrestrial topographic mapping, are examined to investigate the interactions among the physical mechanisms that make up the hydrological cycle and the corresponding physical hydrological processes triggered by deforestation and reforestation in the region. More specifically, the modeling approach was rigorously designed to also consider, separately or not, Negro, Solimões, Madeira, Tapajós and Xingu hydrographic sub-basins, which are the most important ones of the Amazon Basin. The results highlight that in the southern region of the Amazon, specifically within the Madeira river sub-basin, the lowest forest coverage is observed (56.0%), whereas in the northern Negro river sub-basin, the most notable forest coverage is observed (85.0%). The most preserved forest areas, such as the Negro and Solimões river sub-basins, with percentages of 81.9% and 74.2%, respectively, have higher annual rates of precipitation and evapotranspiration over time. On the other hand, regions that suffered the most intense deforestation along the time period studied, such as the Madeira, Tapajós and Xingu sub-basins, have lower annual rates of precipitation and evapotranspiration, with preservation percentages of 54.6%, 62.6% and 70.7%, respectively. As the pace of deforestation slowed between 2003 and 2013, annual precipitation rates increased by 12.0%, while evapotranspiration decreased by 2.0%. The hydrological findings of this paper highlight th predominant role of the forest in the context of the global water balance of the Amazon Basin and the potential to also produce distinct impacts within different parts of the basin in terms of having more or less rainfall and evapotranspiration. In addition, those variabilities in the hydrological operational components and mechanisms due to changes in land cover and land use also reveal the potential impacts that could be expected in the surrounding areas, closer or farther, notably beyond the limits of the Amazon Basin.