The salinization of freshwaters is a global water quality problem that leads to the biological degradation of aquatic ecosystems. However, little is known about the spatial extent of freshwater salinization and the relative contribution of each human activity (e.g. agriculture, urbanization, mining or shale-gas extraction). Here, we investigated environmental factors that explain spatio-temporal patterns of water salinity and examined the causes, the extent and the degree of salinization of Spanish rivers. Results showed a strong variation in water salinity among river typologies and between river reaches in good and poor ecological status according to the Water Framework Directive. The variation in water salinity was largely explained by a combination of natural (i.e. climate and geology) and anthropogenic (i.e. land use) factors. By contrast, land use factors as urbanization and agriculture were the main drivers of salinization, which affected more than one quarter of the rivers and streams in Spain, especially those in the most arid regions (central and southern regions) and in the main courses of the largest rivers such as the Ebro, Douro and Tajo rivers. The information provided here can be relevant to set priority regions and actions to ameliorate freshwater salinization.