The U.S. is in the midst of a public health crisis related to drug overdose deaths. Largely responsible for the dramatic increase in overdose deaths is the misuse of prescription drugs such as opioids and benzodiazepines. While much research attention has focused on correlates of prescription drug misuse in recent years, notable gaps in the literature remain. The current research addresses one of these gaps by examining the relationship between disability status and prescription drug misuse. We examine data from the 2015 National Survey on Drug use and Health, a leading source of epidemiological data on drug use in the United States that added questions related to disability status to the 2015 survey. The current research assessed the relationship between disability status (i.e. activities of daily living and instrumental activities of daily living) and prescription drug misuse (i.e. opioids and benzodiazepines) among adults. Findings from multinomial logistic regression analysis showed that a disability related to activities of daily living was correlated with opioid misuse, while a disability associated with instrumental activities of daily living was associated with benzodiazepine misuse and misuse of both. In addition, health related measures had a greater impact on the relationship between disability status and prescription drug misuse than did the social engagement/isolation measures. Findings indicated that disability status is a significant correlate of prescription drug misuse. However, this relationship was largely mediated by measures associated with poor health and social engagement/isolation. •The current research examined disability status and prescription drug misuse.•Respondents with a disability were at increased odds of prescription drug misuse.•Poor health and social isolation were mediating variables for opioid misuse.•Disability status remained a significant correlate of benzodiazepine misuse.