Few examples of mesopredator release, whereby subordinate predators increase in abundance in response to a reduction in dominant predators, have been demonstrated from reptile communities despite the important ecological role of large varanids and snakes. We tested the hypothesis that trophic cascades attributable to mesopredator release of varanids could explain the apparently perverse decline of some small reptiles following removal of exotic mammalian predators in a landscape-scale reserve in arid South Australia. We used counts of Sand Goanna (Varanus gouldii) tracks and diggings as a surrogate activity index in paddock-scale treatments with different assemblages of feral predators and reintroduced mammals. Varanus gouldii activity was five times higher in regions where cats and foxes were removed than where they were present. We hypothesize that the suppression of mammalian predators can have complex effects that extend to reptile communities and should inform conservation management decisions in environments with large reptile predators.