Invasive animal species are a major factor in the extinction and endangerment of native species worldwide. Longterm monitoring reveals some mammal recoveries have not been sustained in the presence of a broad-scale threat abatement program aimed at reducing the impact of the introduced Vulpes vulpes (red fox)—a top-order predator and key threat to many native species in Australia. Over 51,000 records of 19 terrestrial mammal species reported from a range of survey methods (pitfall traps, Elliott box traps, wire cage traps, spotlighting, sand plots, and nest boxes) across the Upper Warren region of southwestern Australia were used to investigate population changes over 41 years (1974–2014). Since the mid-1990s, populations of at least 7 native mammal species or genera have successively declined at similarly rapid rates and magnitudes (80–100%): Sminthopsis spp., Rattus fuscipes, Phascogale tapoatafa, Isoodon obesulus, Pseudocheirus occidentalis, Bettongia penicillata, and Notamacropus irma. R. fuscipes has not been recorded in the region since 2005 and may have become locally extinct. The other species that have declined remain at risk of becoming locally extinct. Three species have increased since 2000: Trichosurus vulpecula, Dasyurus geoffroii, and Notamacropus eugenii. The Upper Warren region in which this community disassembly has occurred is one of the principal sites for the conservation of many threatened mammal species and is within Australia's global biodiversity hotspot. We discuss the critical importance of long-term monitoring and the need to identify the causes of population change to inform how conservation and management activities can best be focussed. Predation by the introduced Felis catus (cat) is hypothesized as the most likely common or primary cause behind many of the recent declines in the Upper Warren. The integrated reduction of both cats and foxes, conducted within an experimental framework, is the most direct and definitive action to test this and deliver the greatest practical conservation outcomes.