The late Quaternary in North America was marked by highly variable climate and considerable biodiversity loss including a megafaunal extinction event at the terminal Pleistocene. Here, we focus on changes in body size and diet in Neotoma (woodrats) in response to these ecological perturbations using the fossil record from the Edwards Plateau (Texas) across the past 20,000 years. Body mass was estimated using measurements of fossil teeth and diet was quantified using stable isotope analysis of carbon and nitrogen from fossil bone collagen. Prior to ca. 7000 cal yr BP, maximum mass was positively correlated to precipitation and negatively correlated to temperature. Independently, mass was negatively correlated to community composition, becoming more similar to modern over time. Neotoma diet in the Pleistocene was primarily sourced from C3 plants, but became progressively more reliant on C4 (and potentially CAM) plants through the Holocene. Decreasing population mass and higher C4/CAM consumption was associated with a transition from a mesic to xeric landscape. Our results suggest that Neotoma responded to climatic variability during the terminal Pleistocene through changes in body size, while changes in resource availability during the Holocene likely led to shifts in the relative abundance of different Neotoma species in the community.