BACKGROUND Mexican Americans are less likely than non-Hispanic Whites to report prescription drug use. This study explores mediating factors, disparities within chronic conditions, and variations in prescription drug use by nativity. METHODS We analyzed data from the National Health and Nutrition Examination Survey (2005-2016). Using survey-adjusted logistic regression models adjusted for age and gender, we estimated odds ratios (OR) for the association between ethnicity and prescription drug use in the past 30 days. Mediation analyses identified factors explaining this association. We also examined medication use for chronic conditions (diabetes, hypertension, hyperlipidemia, and depression) and variations in use by nativity. RESULTS Mexican Americans had lower odds of using prescription drugs (adjusted OR (aOR) 0.38; 95% CI 0.34-0.42). In mediation analyses, lack of prescription drug coverage (proportion mediated (PM) 34.4%; 95% CI 25.1-46.7) and ≤2 health visits per year (PM 19.9%; 95% CI 13.6-28.1). explained a significant portion of the disparity. Contrastingly, poor health status narrowed the gap (PM -13.8%; 95% CI -16.3- -11.1). Mexican Americans with hypertension (AOR 0.79; 95% CI 0.64-0.96) and depression (AOR 0.50; 95% CI 0.33-0.75) had lower odds of receiving medication. Immigrant Mexican Americans had lower odds of using prescription drugs (aOR 0.25; 95% CI 0.22-0.29) compared to U.S.-born individuals (aOR 0.62; 95% CI 0.54-0.73). CONCLUSIONS This study highlights an unmet treatment need for those with chronic conditions in the Mexican American community, with particularly notable disparities among immigrant Mexican Americans. Addressing these issues is crucial for improving healthcare equity.