The São Francisco River Basin (SFRB) is one of the main watersheds in Brazil, standing out for generating energy and consumption, among other ecosystem services. Hence, it is important to identify hydrological drought events and the anomalous climate patterns associated with dry conditions. The Standard Precipitation Index (SPI) for 12 months was used to identify hydrological drought episodes over SFRB 1979 and 2020. For these episodes, the severity, duration, intensity, and peak were obtained, and SPI-1 was applied for the longest and most severe episode to identify months with wet and dry conditions within the rainy season (Nov–Mar). Anomalous atmospheric and oceanic patterns associated with this episode were also analyzed. The results revealed the longest and most severe hydrological drought episode over the basin occurred between 2012 and 2020. The episode over the Upper portion of the basin lasted 103 months. The results showed a deficit of monthly precipitation up to 250 mm in the southeast and northeast regions of the country during the anomalous dry months identified through SPI-1. The dry conditions observed during the rainy season of this episode were associated with an anomalous high-pressure system acting close to the coast of Southeast Brazil, hindering the formation of precipitating systems.