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Invasive species are a major cause of vertebrate extinctions worldwide, yet there is limited research on their impacts to global patterns of extinction and endangerment in reptiles. We assessed the relative impact of invasive species to extinction risk in native lizards, identified major invasive genera and threat types (e.g., mammalian predator), and examined geographic and ecological correlates of invasive-driven extinction risk using IUCN Red List data. We found that invasive species are the fourth most recorded threat to lizard species yet included the largest number of extinct lizard species of any threat type ( N = 15). An additional 27 species are possibly extinct, indicating that this impact may be substantially greater. At least 128 invasive genera impact native lizards including plants, mammals, reptiles, birds, amphibians, and invertebrates through predation, competition, habitat disruption and/or hybridization. Invasive mammalian predators, especially cats and rats, were the most common threats and associated with most extinctions. Islands were significantly more likely to contain threatened or extinct lizard species, with pronounced hotspots in the Caribbean and Oceania. Deforestation and mammalian habitat disruptors were correlated with significantly higher threat categories for invasive-impacted lizards, while anthropogenically modified landscapes and threats from reptile species were associated with lower extinction risk. Our results place research on invasive-native interactions on lizards into a global context to better understand large-scale patterns. Invasive species currently function as the largest driver of lizard extinction, so management should focus on targeted prevention and control in at-risk hotspots to mitigate this significant threat to global biodiversity.