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Context Today, more than 32% of amphibian species are threatened and more than 43% face a steep decline in numbers. Most species are being affected simultaneously by multiple stressors and habitat protection is often inadequate to prevent declines. Aims The main goal of the present research was to understand the consequences of alternative human land use in producing landscape disturbance for amphibians. At the same time, we also evaluated the effect of changing climatic conditions as additional potential drivers of population decline. Another goal was to determine whether and to what extent the existing nature reserves have been effective in protecting species in recent decades. Methods We used generalised additive models (GAMs) to investigate the association between the state (stable/decline) of amphibian populations in 5×5km cells in central Italy and proxies of different typology of anthropogenic stressors, climatic variables and protection measures. Key results We found a significant association between anthropogenic landscape modifications and species decline. This negative relationship was revealed with agricultural predictors for the majority of the species, whereas urban fabrics had a slightly smaller impact. We found significant associations between amphibian declines and climatic variation, particularly the increasing number of dry days. Protected areas protected declines of two species only. Conclusions Our results showed that the status of amphibians in this region warrants greater attention than has been given previously. The detrimental effect of agricultural practices, combined with increasing aridity, makes amphibian populations particularly susceptible to extinction, and the conservation measures applied till now are inadequate for species protection in this region. Implications Our results should stimulate the implementation of environmental policies that focus not only on the protection of single habitats, but also on ensuring the environmental quality of the surrounding landscapes. Moreover, an adaptive management approach should be applied to take into account future modification of hydrology and climate.