The control exerted by the hydrostratigraphic structure on aquifer recharge, groundwater flow and discharge along the coastal areas of a Mediterranean basin (Salento peninsula, about 5,000 km2 wide, southern Italy) is assessed through the development and application of a groundwater flow model based on the reconstruction of the hydrostratigraphic architecture at the regional scale. The hydrostratigraphic model, obtained by processing surface and subsurface data, is applied to map the top of the main aquifer, which is hosted in the deep hydrostratigraphic unit corresponding to Cretaceous and Oligocene limestones with complex geometrical relationships with the sea. It is also used to estimate the aquifer recharge, which occurs by percolation through overlying younger sediments with low permeability. These data are completed with information about the soil use to estimate water abstraction for irrigation and with literature data to estimate the water abstraction for drinking and industrial purposes. The above-sketched conceptual model is the basis for a finite difference groundwater 2D pseudo-stationary flow model, which assumes the following fundamental approximations: the fractured and karst limestone hydrostratigraphic unit can be approximated, at the model scale, as a continuous medium for which the discrete Darcy’s law is valid; the transition zone between salt and fresh water is so small with respect to the grid spacing that the Ghyben–Herzberg’s approximation for a sharp interface can be applied. Along the coastline different boundary conditions are assigned if the top of the limestone hydrostratigraphic unit lies either above the sea level (the aquifer has a free surface and fresh water is drained), or below the sea level (the aquifer is under pressure and the contact with sea occurs off-shore). The groundwater flow model correctly predicts the areas where the aquifer is fully saturated with salt water.