Pleistocene glaciation events had a dramatic impact on temperate taxa by displacing animal and plant populations south of ice sheets into glacial refugia. Genetic variation often reflects these histories of isolation within glacial refugia and subsequent recolonization. The highly speciose rodent genus Peromyscus, in particular, is well known for its rapid diversification during the Pleistocene. Peromyscus are also significant reservoirs for a myriad of zoonoses, and many cosmopolitan species are undergoing range expansions due to human land use and climate change. This study focused on the range-wide phylogeography of the white-footed mouse (Peromyscus leucopus), a common species found in eastern North America that is one the primary reservoirs for Lyme Disease (Borrelia burgdorferi). We used two mitochondrial genes, cytochrome b and control region, to identify evolutionary lineages of white-footed mice and characterize patterns of expansion of each lineage across their geographic range. Overall, we found evidence for four evolutionary lineages with a Southwest lineage largely restricted to grassland and desert habitats. Time since recent common ancestors placed all lineages diverging within the Last Glacial Maximum (~19-25k years ago). All lineages exhibited signatures of expansion, particularly the two northern lineages known to host Lyme Disease. Overall, white-footed mice underwent rapid diversification similar to other Peromyscus species and potentially exhibit habitat-based divergence within the Southwest lineage. Signatures of expansion also indicate that white-footed mice will continue to facilitate increased spread of zoonoses like Lyme Disease, but further study is needed to clarify how these evolutionary dynamics interact with other factors associated with human disease incidence.