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Eco-cultural landscapes are assumed to be favorable environments for the persistence of biodiversity, but global change may affect differently their terrestrial and aquatic components. Few long-term studies have examined how multiple, global change stressors may affect wetland biodiversity in such environments. Facultative paedomorphosis is a spectacular example of intra-specific variation, in which biphasic (metamorphosing) amphibians coexist with fully aquatic conspecifics that do not metamorphose (paedomorphs). Paedomorphosis is seriously threatened by global change stressors, but it is unknown to what extent traditional management will allow its long-term persistence. Here, we tested the effects of alien species introductions while taking into account land use and climate changes on the distribution of two polymorphic newt species (Ichthyosaura alpestris and Lissotriton graecus) in Montenegro by using a 68-yr data set and Bayesian mixed models integrating complex spatial and temporal structures. We found that, despite the persistence of natural landscapes, metamorphs dramatically declined and paedomorphs were nearly extirpated, losing 99.9% of their aquatic area of occupancy and all the major populations. Fish introduction was the main determinant of decline for both phenotypes. Climate and the presence of crayfish further contributed to the decline of metamorphs, which started later and was less dramatic than that of paedomorphs. The near extinction of paedomorphosis on a country-wide scale shows how invasive species determine broad-scale impacts, which can be even stronger than other global change stressors, and underlines the need for immediate management actions to avoid the extinction of a unique developmental process, paedomorphosis.