Although protected areas (PAs) are considered fundamental to the conservation of nature, exotic species (ES) impose challenges on their role as biodiversity reservoirs, especially under climate change scenarios. In this regard, PAs of temperate & non-tropical countries of the Southern Hemisphere, like Chile, may be particularly vulnerable to ES due to the high endemism plus the expense due to control programs of exotic species and of the environmental conditions suitable for them. Here, we evaluated how vulnerable PAs are to the exposure of some of the “100 of The World’s Worst Invasive Alien Species”, which include animals and plants introduced in Chile, by combining climate change scenarios and ecological niche modeling. We projected the niche requirement of these exotic species on two alternative emission scenarios with varying levels of mitigation by 2050. We found that the central-southern and southern macro-regions are the most susceptible to be invaded in mainland Chile, with the occurrence of at least 80% of evaluated species. National Reserves (homologated with category IV IUCN) of the central and southern regions were the PAs most exposed sites to the spread of the evaluated species under climate change scenarios. These findings provide helpful evidence of the vulnerability of Chilean PAs and important insights into the need for urgent management intended to avoid future climate change-induced establishment of exotic species.