The prevalence of older adults with pain and comorbid cardiovascular conditions is increasing in the United States (U.S.). This retrospective, cross-sectional database study used 2017 Medical Expenditure Panel Survey data and hierarchical logistic regression models to identify predictive characteristics of opioid use among a nationally representative sample of older U.S. adults (aged ≥50 years) with pain in the past four weeks and comorbid hypertension (pain–hypertension group) or hypercholesterolemia (pain–hypercholesterolemia group). The pain–hypertension group included 2733 subjects ( n = 803 opioid users) and the pain–hypercholesterolemia group included 2796 subjects ( n = 795 opioid users). In both groups, predictors of opioid use included: White race versus others, Hispanic versus non-Hispanic ethnicity, 1 versus ≥5 chronic conditions, little/moderate versus quite a bit/extreme pain, good versus fair/poor perceived mental health, functional limitation versus no functional limitation, smoker versus non-smoker, and Northeast versus West census region. In addition, Midwest versus West census region was a predictor in the pain–hypertension group, and 4 versus ≥5 chronic conditions was a predictor in the pain–hypercholesterolemia group. In conclusion, several characteristics of older U.S. adults with pain and comorbid hypertension or hypercholesterolemia were predictive of opioid use. These characteristics could be addressed to optimize individuals’ pain management and help address the opioid overdose epidemic.