Yersinia pestis invaded the continental United States in 1900 and subsequently became established in wild rodent populations in several western states, traversing 2,250 km in approximately 40 years. However, the specific path of the eastward expansion of plague into the United States is poorly understood. We directly calculated velocities of disease spread and performed trend-surface analyses on spatio-temporally unique plague cases to clarify the route and speed of the initial spread of plague eastward. Velocities of disease spread were then analyzed using multiple linear regression models to identify environmental features that significantly impacted the rate of spread. Between one and three introductions of plague along the Pacific coast were observed, after which plague traveled from 45 to 87 km/year. In all regression models, the coast ranges of California were associated with slower spread, and the Southern Rockies were associated with a significant increase in the rate of disease spread. Additional climatic and environmental factors affecting the velocity of plague's spread varied among the models. Maps were developed to graphically represent the traveling waves of plague over the United States landscape. These analyses identify important large-scale trends regarding the eastward invasion of plague into the continental United States that can be used to better understand the historical spread of plague, as well as how to manage threats from new or re-emerging diseases that might operate under similar spatio-temporal dynamics.