AbstractDefaunation is an increasingly pervasive process, reaching ever larger spatial scales worldwide. We integrated data on thousands of putative local mammal assemblages across the Neotropics into 518 metacommunities to predict the phylogenetic trait‐based effects of regional defaunation—here defined as meta‐extirpation (i.e. extinction at the metacommunity level)—on dozens of putative ecosystem services (ESs). Further, based on 1029 real‐world mammal assemblages coalesced into 236 metacommunities, we assessed the spatial extent of meta‐extirpations across the Neotropics, while empirically quantifying losses in ESs in comparison with putative scenarios. Using observed data, we also sought to understand changes in the mean body size of metacommunities for different dietary guilds. We examined patterns of mammal diversity, evaluated the erosion of ESs based on ecological networks and measured the relationships between diversity metrics and ESs via dissimilarity arrangements and generalized linear models. Meta‐extirpation regimes lead to a mean loss of 49.6% of the ESs provided by Neotropical mammals within metacommunities, whereas real‐world meta‐extirpations derived 47.2% of ES loss. We show that simulated meta‐extirpations penalizing large‐bodied species, induced the most severe losses in ESs. Regional‐scale meta‐extirpations lead to changes in the metabolic allometry and trophic structure of consumers, inducing significant metacommunity downsizing. We conclude that once‐thriving mammal‐mediated roles in natural ecosystems are fading, with significant consequences for human livelihoods. Many mammal populations have succumbed in several Neotropical ecoregions; so it is critical to protect representative fractions of Neotropical landscapes and regional species pools. Finally, we reinforce the appeal for effective conservation action, given that meta‐extirpations are already a global reality.