Macroecological analyses capture the widespread nature of wild mammal range contractions and population declines globally, with Neotropical rainforests particularly vulnerable. Yet there is a paucity of basic population biology data capturing local empirically observed population changes. We generated species-specific and aggregated temporal trends in populations of terrestrial mammals in Cusuco National Park, north-west Honduras testing the effects of body-size, hunting and zonal protection measures. Hunted species, regardless of body size, exhibited declines (ca. -7% per year) with greater rapidity of decline in the park’s more accessible and less rigorously protected buffer zone. The site was once regarded as a remaining strong of Baird’s tapir (Tapirus bairdii), IUCN Red Listed as Endangered, but our data suggest its near local extirpation from monitored sites. Hunted deer (Mazama temama and Odocoileus virginianus) and paca (Cuniculus paca) also declined substantially. Whilst species-specific trends varied among unhunted species (e.g. wild cats, mustelids etc.) they, nevertheless, also exhibited an aggregated decline throughout the park (ca. -6% per year). Such was the rapidity of these declines that we estimate substaintial mammalian defaunation of Cusuco National Park by the mid-2020s leaving a notionally highly protected area mostly devoid of terrestrial mammals and the associated ecosystem services they deliver (so-called ‘empty forest syndrome’). We call on Governments and non-governmental organizations including conservation charities to prioritize urgent efforts to secure funding and personnel to ensure designated areas are adequately protected with enforcement of existing legislative protection whether through patrols or capacity building to efficiently curtail ongoing defaunation.