The Paraiba do Sul River Basin (PSRB) is a vital source of water resources in Brazil, providing water for human consumption, industry, agriculture, and hydroelectric energy generation. As part of one of the most developed areas of the country, in the Southeast of Brazil, the region is vulnerable to the impacts of climate change, with evidence of extreme events such as droughts and floods affecting the availability and quality of water. Hence, this study analyzes precipitation and streamflow rates data from the PSRB between 1939–2020 to investigate the spatial variability of average patterns and extreme events, trends, and their relationship with urban growth and socioeconomic development. The analysis reveals significant spatial variations in precipitation and runoff rates, with higher altitude areas, such as the Serra da Mantiqueira, exhibiting higher average values. Moreover, the Mann–Kendall trend results showed in most of the sites no significant trend regarding precipitation data; however, about 50% of the sites in the PSRB presented a decreasing trend of runoff rates. Since the precipitation does not explain identified changes in the hydrological patterns, the evaluation of the area’s urban growth and socioeconomic development throughout the decades suggested that human activities, such as those associated with urbanization, have played a significant role in altering the runoff patterns in the basin. These findings highlight the importance of sustainable land-use planning and water resource-management practices in the PSRB to mitigate the negative impacts of urbanization on the hydrological cycle and to enhance the resilience of the region’s water resources.