The La Plata basin is one of the largest river basins in the world, draining about a fifth of the South American continent. It is a system of great hydrological significance, sensitive to extreme events, and also has the most economic development in the region. This work analyses the total water storage (TWS) changes over the La Plata basin from the GRACE (Gravity Recovery And Climate Experiment) mission and compares it with TRMM (Tropical Rainfall Measuring Mission) rainfall data. Subsequently, a study was conducted on the main sub-basins for the period 2003 to 2017 to identify regional-scale variations in TWS. Precipitation and GLDAS (Global Land Data Assimilation System) runoff data was evaluated in these areas, along with their connections to ENSO (El Niño Southern Oscillation) episodes. The results suggest that the majority of TWS variations are associated with extreme climatic events, such as the 2009 drought, and are linked to ENSO periods. The statistical analysis indicates a significant correlation between severe Niño/Niña episodes and changes in TWS in the sub-basins.