Predators are fundamentally important in regulating many global ecosystems, and perturbations of predator populations through impacts by invasive species are frequently implicated in the degradation of these ecosystems. In considering recent declines of native critical weight range (35–5500 g) mammals in northern Australia, most attention has focused on predator–prey interactions between a mammalian invader, the feral cat (Felis catus), and these mammals. Little consideration has been given to the possible implications of changed reptilian predator assemblages resulting from invasion by another vertebrate, the toxic cane toad (Rhinella marina). We used reptile removal records from licenced reptile catchers in three widely spaced towns in the savannas of northern Australia to explore potential impacts of toads on apex and meso-predatory snakes and large lizards. In addition, simultaneous fauna survey data from one town with reptile removal records were used to identify cascading faunal impacts associated with toad invasion. Intervention analyses revealed empirical linkages between toad invasion, apex predator declines, meso-predator increases and declines of critical weight range mammals and other prey groups. Based on the timing and strength of intervention we postulate a novel hypothesis and supporting conceptual model linking recent mammal declines with trophic cascades following toad invasion. The conceptual model is discussed in relation to the prevailing feral cat focussed hypotheses regarding northern Australia’s dramatic small mammal declines. Future studies will need to test putative interactions and their importance so that appropriate management can be implemented to stem ongoing mammal losses.