Identifying the factors that determine the spatial distribution of biodiversity is a major focus of ecological research. These factors vary with scale from interspecific interactions to global climatic cycles. Wetlands are important biodiversity hotspots and contributors of ecosystem services, but the association between proportional wetland cover and species richness has shown mixed results. It is not well known as to what extent there is a relationship between proportional wetland cover and species richness, especially at the sub-continental scale. We used the National Wetlands Inventory to model wetland cover for the conterminous United States and the National Land Cover Database to estimate wetland change between 2001 and 2011. We used a Bayesian spatial Poisson model to estimate a spatially varying coefficient surface describing the effect of proportional wetland cover on the distribution of amphibians, birds, mammals, and reptiles and the cumulative distribution of terrestrial endemic species. Species richness and wetland cover were significantly correlated, and this relationship varied both spatially and by taxonomic group. Rather than a continental-scale association, however, we found that this relationship changed more closely among ecoregions. The species richness of each of the five groups was positively associated with wetland cover in some or all of the Great Plains; additionally, a positive association was found for mammals in the Southeastern Plains and Piedmont of the eastern U.S. Model results indicated negative association especially in the Cold Deserts and Northern Lakes & Forests of Minnesota and Wisconsin, though these varied greatly between groups. Our results highlight the need for wetland conservation initiatives that focus efforts at the level II and III ecoregional scale rather than along political boundaries.