Brine and petroleum spills may affect terrestrial vertebrates through loss of reproductive habitat or reduced food availability rather than direct toxicity. A proposed ecological framework for evaluating impacts of these spills includes individual-based population models, a site conceptual trophic model, habitat suitability maps, and a stochastic brine spill generator. Simulation results for mammal populations in the Tallgrass Prairie Preserve petroleum exploration and production (E&P) site in Oklahoma are presented. The persistence of simulated American badger (Taxidea taxus) populations decreased with increasing brine spill area. The decline in persistence and average final population size was much steeper in highly fragmented landscapes. The simulated time to extinction for prairie vole (Microtus ochrogaster) populations showed a threshold at 30% habitat loss from spills; above this threshold the time to extinction decreased with increasing spill area. Vole density was sensitive to the interaction of predation and fragmentation, with fragmentation causing population extinction in the presence of predation, yet stabilizing the population in the absence of predation. We anticipate that our results will aid in future development of “exclusion criteria” for leaving unrestored habitat at E&P sites.