This retrospective cross-sectional database study used 2018 Medical Expenditure Panel Survey data to quantify and assess differences in healthcare expenditures between opioid users and non-users among a non-institutionalized sample of older (≥50 years) United States adults with pain in the past four weeks and a diagnosis of comorbid hypercholesterolemia (pain-hypercholesterolemia group) or hypertension (pain-hypertension group). Hierarchical multivariable linear regression models were constructed by using logarithmically transformed positive cost data and adjusting for relevant factors to assess cost differences between groups. Percent difference between opioid users and non-users was calculated by using semi-logarithmic equations. Healthcare costs included inpatient, outpatient, office-based, emergency room, prescription medication, other, and total costs. In adjusted analyses, compared to non-users, opioid users in the pain-hypercholesterolemia and pain-hypertension groups respectively had 66% and 60% greater inpatient expenditure, 46% and 55% greater outpatient expenditure, 67% and 72% greater office-based expenditure, 50% and 60% greater prescription medication expenditure, 24% and 22% greater other healthcare expenditure, and 85% and 93% greater total healthcare expenditure. In conclusion, adjusted total healthcare expenditures were 85-93% greater among opioid users versus non-users in older United States adults with pain and comorbid hypercholesterolemia or hypertension. Future research is needed to identify opioid use predictors among these populations and reduce expenditures.