Estuaries are highly dynamic, complex and one of the most productive ecosystems in the world. In the Patos Lagoon estuary, which is connected to the South Atlantic Ocean through a single inlet, the saltwater transport into and out of the estuary is intimately connected to the wind and river discharge from the main tributaries, as tidal effects are small and restricted to the lower region of the lagoon (estuary). However, little is known about the spatio-temporal variability of salinity within the lagoon itself, making it the focus of this study. Salinity variability was investigated over a five-year period (2002–2006) applying the TELEMAC-3D numerical model. After calibration and validation, model results were compared to river discharge and wind time series to identify correlations with salinity variations along the estuary. Wavelet analysis was applied to time series of salinity and indicated that river discharge influences salinity patterns at long time scales (> 128 days), while synoptic forcing modulates its variability at shorter timescales (< 15 days). Results also show that in years of higher river discharge and NE wind predominance (El Niño), salty waters are pumped out of the estuary. On the other hand, in years of lower river discharge and SW wind predominance (La Niña), salty waters are pumped into the estuary. Thus, on an interannual timescale, El Niño Southern Oscillation (ENSO) cycles influence salinity variability in Patos Lagoon, since it changes atmospheric conditions (winds and precipitation) and, consequently, river discharge.