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The viewpoint and reaction of a country towards climate change are shaped by its political, cultural, and scientific backgrounds, in addition to the distinct characteristics of its evolving climate and the anticipated and actual consequences of the phenomenon in the times ahead. A regions climate has a significant impact on how water is managed and used, mostly in the primary sector, and both the distribution of ecosystem types and the amount and spreading of species on Earth. As a result, the environment and agricultural practices are affected by climate, so evaluating both distribution and evolution is extremely pertinent. Towards this aim, the climate distribution and evolution in the São Francisco River basin (SFRB) is assessed in three periods (19702000, 19812022) in the past and 20412060 in the future from an ensemble of GCMs under two SSPs (Shared Socioeconomic Pathways), SSP2-4.5 and SSP5-8.5. The Köppen-Geiger (KG) climate classification system is analyzed, and climate change impacts are inferred for this watershed located in central-eastern Brazil, covering an area equivalent to 8% of the country. Results predict the disappearance of the hot summer (Csa) and warm summer (Csb) Mediterranean climates, and a reduction/increase in the tropical savanna with dry winter (Aw)/dry summer (As). A striking increase in the semi-arid hot (BSh-steppe) climate is predicted with a higher percentage (10%) under SSP5-8.5. The source and the mouth of SFRB are projected to endure the major impacts of climate change that are followed by a predicted increase/decrease in temperature/precipitation. Future freshwater resource availability and quality for human use will all be impacted. Consequences on ecosystems, agricultural, and socioeconomic sectors within the SFRB might deepen the current contrasts between regions, urban and rural areas, and even between population groups, thus translating, to a greater extent, the inequality that still characterizes Brazilian society. Maps depicting land use and cover changes in SFRB from 1985 to 2022 highlight tendencies such as urbanization, agricultural expansion, deforestation, and changes in shrubland and water bodies. Urban areas fluctuated slightly, while cropland significantly increased from 33.57% to 45.45% and forest areas decreased from 3.88% to 3.50%. Socioeconomic data reveals disparities among municipalities: 74.46% with medium Human Development Index (HDI), 0.59% with very high HDI, and 9.11% with low HDI. Most municipalities have a Gross Domestic Product (GDP) per capita below US$6000. Population distribution maps show a predominance of small to medium-sized urban and rural communities, reflecting the basins dispersed demographic and economic profile. To achieve sustainable adaptation and mitigation of climate change impacts in SFRB, it is imperative that integrated measures be conducted with the cooperation of stakeholders, the local population, and decision-makers.