Geographical Isolated Wetlands (GIWs) are surrounded by uplands, lack persistent surface water connections and are characterized by slow or episodic organism exchange. While considered isolated, GIWs are important components of wetland networks. We used a theoretical modelling approach to analyze different wetland network configurations and to identify the “keystone” wetlands of the network, defined as those wetlands that experience highest rates of species loss due to either loss of wetland habitat or loss of biological connectivity. Wetland networks were virtually generated and represented using graph theory, including nodes (wetlands) and links (flows of organisms between wetlands). Graphs were coupled with a model of population dynamics that simulated the evolution of two amphibian species with distinct life cycle traits– Northern Leopard Frog (Lithobates pipiens) that requires a more aquatic habitat and Great Plains Toad (Bufo cognatus) that requires a more terrestrial habitat– in each wetland. Geometrical properties of the network were correlated with species density within the network. We found that the optimal wetland configuration differed for each species, reflecting their dispersal capacities; and the number of wetland connections was positively correlated with amphibian density. Removal of any wetland results in population decline, but removal of keystone wetlands results in the highest rates of decline, due to a loss of biological connectivity. Our theoretical modelling approach enabled identification of “keystone” GIWs that are strategic for the resilience of the network, as well as “thresholds” in wetland removal that place at risk the vulnerable species.