The catastrophic loss of large-bodied mammals during the terminal Pleistocene likely led to cascading effects within communities. While the extinction of the top consumers probably expanded the resources available to survivors of all body sizes, little work has focused on the responses of the smallest mammals. Here, we use a detailed fossil record from the southwestern United States to examine the response of the hispid cotton rat (Sigmodon hispidus) to biodiversity loss and climatic change over the late Quaternary. In particular, we focus on changes in diet and body size. We characterize diet through carbon (d¹³C) and nitrogen (d¹⁵N) isotope analysis of bone collagen in fossil jaws and body size through measurement of fossil teeth; the abundance of material allows us to examine population level responses at millennial scale for the past 16ka. Sigmodon was not present at the cave during the full glacial, first appearing at ~16ka after ice sheets were in retreat. It remained relatively rare until ~12ka when warming temperatures allowed it to expand its species range northward. We find variation in both diet and body size of Sigmodon hispidus over time: the average body size of the population varied by ~20% (90-110g) and mean d¹³C and d¹⁵N values ranged between -13.5 to -16.5‰ and 5.5 to 7.4‰ respectively. A state-space model suggested changes in mass were influenced by diet, maximum temperature and community structure, while the modest changes in diet were most influenced by community structure. Sigmodon maintained a fairly similar dietary niche over time despite contemporaneous changes in climate and herbivore community composition that followed the megafauna extinction. Broadly, our results suggest that small mammals may be as sensitive to shifts in local biotic interactions within their ecosystem as they are to changes in climate and large-scale biodiversity loss.