Lizards play vital roles in extant ecosystems. However, their roles in extinct ecosystems are poorly understood because the fossil record of lizards consists mostly of isolated bones. This makes it difficult to document changes in lizard morphology and body size over time, which is essential for studies of lizard paleoecology and evolution. It is also difficult to compare available fossil lizard data with existing sources of extant lizard data because extant studies rarely measure individual bones. Furthermore, no previous study has regressed measurements of individual bones to body length across crown lizard groups, nor tested those regressions on fossil skeletons. An extensive dataset of individual bone measurements from extant lizards across crown taxonomic groups is here employed to develop novel methods for estimating lizard body size from isolated fossil elements. These methods were applied to a comparably large dataset of fossil lizard specimens from the robust Paleogene record (66–23 Ma) of the Western Interior of North America. This study tests the hypothesis that anatomical proportions have been conserved within higher-level crown lizard groups since the Paleogene and can therefore be used to reconstruct snout-vent length (SVL) and mass for fossil specimens referred to the same groups. Individual bones demonstrated strong correlation with SVL in extant as well as fossil lizard specimens (R2 ≥ 0.69). Equations for mass estimation from individual bones were derived from the SVL regressions using published equations for calculating lizard body mass from SVL. The resulting body size estimates from regression equations for the entire fossil dataset revealed that lizards reached greatest maximum body size in the middle Paleogene, with the largest size class dominated by anguid lizards that exceeded 1 meter in SVL and 1.5 kg in body mass. Maximum body size decreased to under 400 mm and below 1.5 kg in the late Paleogene. No association was found between changes in maximum lizard body size and marine isotope proxies of global temperature through the Paleogene. This is the first study to investigate body size evolution across lizard clades over a deep time interval and for a large geographic region. The proposed methods can be used to generate body size regressions and provide estimates of body size for isolated lizard bones referred to any crown group.