In July 2002, lightning strikes ignited over 250 fires in Quebec, Canada, destroying over one million hectares of forest. The smoke plume generated from the fires had a major impact on air quality across the east coast of the U.S. Using data from the Medicare National Claims History File and the U.S. Environmental Protection Agency (EPA) National air pollution monitoring network, we evaluated the health impact of smoke exposure on 5.9 million elderly people (ages 65+) in the Medicare population in 81 counties in 11 northeastern and Mid-Atlantic States of the US. We estimated differences in the exposure to ambient PM2.5—airborne particulate matter with aerodynamic diameter of ≤2.5 µm—concentrations and hospitalizations for cardiovascular, pulmonary and injury outcomes, before and during the smoke episode. We found that there was an associated 49.6% (95% confidence interval (CI), 29.8, 72.3) and 64.9% (95% CI, 44.3–88.5) increase rate of hospitalization for respiratory and cardiovascular diagnoses, respectively, when the smoke plume was present compared to before the smoke plume had arrived. Our study suggests that rapid increases in PM2.5 concentrations resulting from wildfire smoke can impact the health of elderly populations thousands of kilometers removed from the fires.