We aimed to identify differences in prescription opioid-related behaviors between adults with and without disabilities in the U.S. We analyzed data from the 2015-2017 National Survey on Drug Use and Health (128,740 individuals; weighted N of 244,831,740) to examine disability-based differences in (1) reasons and sources of last prescription opioid misuse and, in multivariate models overall and stratified by disability, the likelihood of (2) prescription opioid use, and if used, (3) misuse and prescription opioid use disorder (OUD), overall and stratified by disability. Adults with disabilities were 11% more likely than adults without disabilities to report any past-year prescription opioid use, adjusted for sociodemographic, health, and behavioral health characteristics. However, among adults with any prescription opioid use, which is more common among people with disabilities, likelihood of prescription OUD did not vary by disability status. Pain relief as the reason for last misuse was associated with 18% increased likelihood of prescription OUD, if any use. To reduce risk of opioid misuse among people with disabilities, accessible and inclusive chronic pain management services are essential. Further, the substance use treatment field should provide accessible and inclusive services, and be aware of the need for pain management by many people with disabilities, which may include the use of prescription opioids. These findings highlight essential opportunities for public health and policies to improve access, accommodations, and quality of health and behavioral health care for people with disabilities, and to encourage a holistic perspective of people with disabilities and their needs.