Determining the environmental and ecological drivers of variation in mammalian life histories is essential for effectively monitoring responses of these taxa to global change. We investigated relationships between climate and an integral life history trait (litter size) in the geographically widespread North American deer mouse (Peromyscus maniculatus). Using a spatiotemporally comprehensive data set of P. maniculatus embryo counts assembled from digitized museum specimens and small mammal census records (> 2,000 observations spanning more than a century), we modeled the associations of litter size with short- and long-term climate variables, and tested for shifts in litter size in response to recent climate change. Litter size in P. maniculatus was correlated with length of the frost-free period, suggesting the former trait may have evolved partly as a response to abiotic or resource-driven constraints on the number of annual breeding opportunities. Short-term climate variables (temperature and precipitation during breeding) were significant predictors of litter size in some models; however, all short-and long-term climate variables other than number of frost-free days added marginal predictive power. Further analyses confirmed age-structured breeding in the most seasonal regions, where maternal body sizes and litter sizes both decrease within a year, although maternal body size itself was poorly predictive of litter size in these populations. We also found a statistically significant decrease in P. maniculatus litter size through time and across known frost-free period regimes (pre- and post-1980), as predicted if longer frost-free periods are increasing lifetime breeding opportunities in this species, although more work is required to confirm this trend and identify underlying mechanisms. Our study refines understanding of climate impacts on P. maniculatus life history and reiterates the great potential of digitized specimen data to help address outstanding questions in mammalian life history and climate change response.