Invasive predators, land clearing and altered fire regimes have been implicated in species decline and extinction worldwide. Enhanced knowledge of how these factors interact and influence medium-sized mammals is warranted. We tested three hypotheses using occupancy data for a diverse mammal assemblage including three threatened species, five common species, two introduced mesopredators and an apex predator in eastern Australia. We hypothesised that occupancy of mammal species within the assemblage would be influenced by (i) the physical environment (rainfall, vegetation type and elevation), (ii) habitat disturbance (number of fires and habitat fragmentation) and (iii) mesopredator release, whereby occupancy and/or detection of medium-sized mammals are influenced by mesopredators, the feral cat (Felis catus) and the red fox (Vulpes vulpes), which are influenced by an apex predator, the dingo (Canis familiaris). We utilised camera-trapping data from 173 sites (692 camera locations) across a north–south gradient spanning ~ 1500 km in eastern Australia. Although hypotheses i (physical environment) and ii (habitat disturbance) are not mutually exclusive, we show that the variables considered in each were only weakly correlated. We conducted occupancy modelling to investigate the physical environment and habitat disturbance hypotheses. We conducted co-occurrence modelling to investigate interactions between species. The physical environment hypothesis best supported occupancy models for six mammal species: red-necked pademelon (Thylogale thetis), bandicoots (Isoodon macrourus and Perameles nasuta), swamp wallaby (Wallabia bicolor), red-necked wallaby (Macropus rufogriseus), eastern grey kangaroo (Macropus giganteus) and feral cat. The disturbance hypothesis best supported occupancy models for four mammal species: long-nosed potoroo (Potorous tridactylus), red-necked pademelon and both mesopredators. Support for the mesopredator release hypothesis was equivocal. Large macropods showed site avoidance towards the red fox. Four species showed higher detection at sites where mesopredators were not detected. The fox showed a negative detection interaction to the dingo and the cat did not. Our study highlights how factors such as rainfall, land clearing, elevation and number of fires influence the occupancy of species within a diverse mammal assemblage at the macroecological scale. Our findings have implications for the conservation of threatened species in managed landscapes and suggestions for further research following the recent 2019–2020 wildfires.