Poikilothermic vertebrates such as lizards can offer viable proxies for terrestrial climate based on measurable relationships between environment and body size. Ambient temperature constrains body size in extant lizards, but this relationship has not been tested in extinct forms through geologic time. In this study, we estimate mean annual paleotemperature (MAPT) based on hypothesized physiological requirements for glyptosaurine lizards (Squamata: Anguidae) according to body size. We show that these MAPT estimates correspond to known floral and isotopic records of continental climate change through the Paleogene of the Great Plains and the Western Interior. We modeled the relationship between skull length and snout-vent length (SVL) for extant anguimorphs and used these models to estimate SVL in glyptosaurines based on fossil cranial material. We then applied the model relationship between mass-specific metabolic rate, maximum SVL and minimum mean annual temperature for extant Heloderma, the largest North American anguimorph, to body size estimates of glyptosaurines to estimate paleotemperatures through the North American Paleogene. We find that maximum body size remained approximately constant among the largest glyptosaurines through the Eocene, with estimated MAPT of about 19 – 21°C in the Great Plains and Western Interior during this interval. Our estimates indicate that maximum body sizes of Oligocene glyptosaurines were less than half of those of the largest Eocene glyptosaurines, corresponding to a significant cooling period in the same region. Our results are consistent with other local proxies for the Paleogene of North America, indicating that body size in fossil lizards can be a useful proxy for estimating terrestrial paleotemperatures over geologic timescales.