This cross-sectional study included a nationally representative sample of U.S. adults aged ≥50 years with self-reported pain in the past 4 weeks from the 2018 Medical Expenditure Panel Survey. Adjusted linear regression analyses accounted for the complex survey design and assessed differences in several types of annual health care expenditures between individuals who reported frequent exercise (≥30 min of moderate-vigorous intensity physical activity ≥5 times per week) and those who did not. Approximately 23,940,144 of 56,979,267 older U.S. adults with pain reported frequent exercise. In adjusted analyses, individuals who reported frequent exercise had 15% lower annual prescription medication expenditures compared with those who did not report frequent exercise (p = .007). There were no statistical differences between frequent exercise status for other health care expenditure types (p > .05). In conclusion, adjusted annual prescription medication expenditures were 15% lower among older U.S. adults with pain who reported frequent exercise versus those who did not.