Droughts reduce freshwater availability and have negative environmental, economic, and social impacts. In estuaries, the dynamics between the saltwater and the freshwater can be affected during droughts, which can impact several natural resources and economic sectors negatively. The Tagus estuary is one of the largest estuaries in Europe and supports diverse uses and activities that can be affected by the saltwater intrusion (e.g., agriculture). This study assesses the saltwater intrusion in the upper reaches of the Tagus estuary using a process-based model to explore different scenarios of freshwater discharge and sea level rise. For the river discharge and mean sea level rise scenarios analyzed, salinity can reach concentrations that are inadequate for irrigation when the mean Tagus river discharge is similar or lower than the ones observed during recent droughts (22–44 m³/s). Lower river discharges aggravate the consequences. Results also show that the salinity increases with the duration of the droughts. In contrast, the impact of a moderate sea level rise on salinity intrusion is modest when compared with the impact of low river discharges. These findings contribute to support the management of the agricultural activities in the upper Tagus estuary and the water resources in the Tagus river basin.