AbstractVariation in genome size spans multiple orders of magnitude among animals. Despite the longstanding debate regarding the adaptive value or costs of genomic complexity, genome size has been proposed to influence extinction risk under the rapidly changing environments of the Anthropocene.The main hypothesis suggests that genome enlargement increases the accumulation of deleterious mutations while reducing rates of organismal growth and development. These combined effects of larger genome size are predicted to trigger population declines that can lead to extinction, especially under rapidly changing environments that disrupt demographic resilience.Comparative evidence from terrestrial plants and across vertebrates has provided mixed support for this hypothesis. However, large‐scale comparative studies based on explicit phylogenetic approaches remain lacking. Using a global‐scale amphibian dataset and two recognised proxies of extinction risk (International Union for Conservation of Nature IUCN conservation categories and population trends), we test the prediction that genomes are larger (as estimated by C‐value) in species facing extinction risk. We combine these analyses with life‐history traits widely known to be implicated with extinctions (body size, fecundity), along with a range of environmental factors.Our phylogenetic analyses consistently failed to identify an effect of genome size on either of the two proxies for extinction risk. The only consistent predictor of extinction risk observed across models performed for amphibians combined and for orders separately was decreasing geographical range size. We also identified a role for larger body size, decreasing range of environmental temperature (for anurans) and increasing levels of UV‐B radiation (for salamanders) as drivers of increasing threat.Our study provides no support for the prediction that species with larger genomes suffer heightened risk of extinction. We discuss some fundamental limitations underlying the genome size‐extinction hypothesis, and suggest that it is not a promising avenue to elucidate the causes of biodiversity declines in the Anthropocene.Read the freePlain Language Summaryfor this article on the Journal blog.