Comparative landscape genetics studies can provide key information to implement cost-effective conservation measures favoring a broad set of taxa. These studies are scarce, particularly in Mediterranean areas, which include diverse but threatened biological communities. Here we focus on Mediterranean wetlands in central Iberia and perform a multi-level, comparative study of two endemic pond-breeding amphibians, a salamander (Pleurodeles waltl) and a toad (Pelobates cultripes). We genotyped 411 salamanders from 20 populations and 306 toads from 16 populations at 18 and 16 microsatellite loci, respectively, and identified major factors associated with population connectivity through the analysis of three sets of variables potentially affecting gene flow at increasingly finer levels of spatial resolution. Topographic, land use/cover, and remotely sensed vegetation/moisture indices were used to derive optimized resistance surfaces for the two species. We found contrasting patterns of genetic structure, with stronger, finer-scale genetic differentiation in Pleurodeles waltl, and notable differences in the role of fine-scale patterns of heterogeneity in vegetation cover and water content in shaping patterns of regional genetic structure in the two species. Overall, our results suggest a positive role of structural heterogeneity in population connectivity in pond-breeding amphibians, with habitat patches of Mediterranean scrubland and open oak woodlands (“dehesas”) facilitating gene flow. Our study highlights the usefulness of remotely sensed continuous variables of land cover, vegetation and water content (e.g., NDVI, NDMI) in conservation-oriented studies aimed at identifying major drivers of population connectivity.