Human-induced habitat changes may lead to the breakdown of reproductive barriers between distantly related species. This phenomenon may result in fertile first-generation hybrids (F1) that exclude the genome of one parental species during gametogenesis, thus disabling introgression. The species extinction risk associated with hybridization with genome exclusion is largely underappreciated because the phenomenon produces only F1 hybrid phenotype, leading to the misconception that hybrids are sterile and potentially of minor conservation concern. We used a simulation model that integrates the main genetic, demographic, and ecological processes to examine the dynamics of hybridization with genome exclusion. We showed that this mode of hybridization may lead to extremely rapid extinction when the process of genome exclusion is unbalanced between the interbreeding species and when the hybridization rate is not negligible. The coexistence of parental species was possible in some cases of asymmetrical genome exclusion, but show this equilibrium was highly vulnerable to environmental variation. Expanding the exclusive habitat of the species at risk allowed its persistence. Our results highlight the extent of possible extinction risk due to hybridization with genome exclusion and suggest habitat management as a promising conservation strategy. In anticipation of serious threats to biodiversity due to hybridization with genome exclusion, we recommend a detailed assessment of the reproductive status of hybrids in conservation programs. We suggest such assessments include the inspection of genetic content in hybrid gametes.