Salinity has been identified as a key variable affecting the distribution of aquatic organisms and influencing critical physiological processes. In sandy beach environments, variations in salinity resulting from local freshwater discharges have shown to produce dramatic effects in the habitat and the resident macrofauna. However, macroscale effects of salinity on sandy beach macrofauna have not been assessed yet. Here, we describe large-scale (400 km) variations in species richness and abundance along a full salinity gradient generated by the Río de la Plata estuary in the south-western Atlantic Ocean. Two-year data assembled from 16 Uruguayan sandy beaches spanning a continuum from reflective to dissipative states were used to model variations in species richness and abundance as a function of salinity and beach morphodynamics. Environmental variables were highly correlated, showing a strong increase (linear or nonlinear) in swash/beach width, wave height and wave period towards oceanic beaches. The association between mean salinity and salinity range was best explained by a quadratic relationship, meaning highest variability at intermediate salinities (14–24). Species richness clearly increased with salinity, swash width and the compound index of beach state Ω (Dean's parameter), and markedly decreased with salinity range and beach face slope. A multiple stepwise regression model that explained 89% of the variance in species richness, included salinity range and beach width as the most important predictor variables. Total abundance increased from estuarine to oceanic beaches and from reflective to dissipative ones. Multiple regression analysis incorporated five environmental variables as main predictors: in addition to salinity range, the model included grain size, sorting, penetrability and organic matter content of the sediment. We conclude that salinity variability is a key factor affecting sandy beach morphodynamics and shaping macroscale patterns in species richness. Alternatively, concurrent variations in salinity and sedimentological variables shape the spatial distribution of total abundance in sandy beach macrofauna.