Prescription opioid misuse among persons with chronic pain is an emerging public health threat of epidemic proportions. We conducted a randomized controlled trial of Mindfulness-Oriented Recovery Enhancement, a multimodal intervention designed to simultaneously target mechanisms underpinning chronic pain and opioid misuse. In this study, a sample of 115 chronic pain patients who were taking long-term opioids were randomly assigned to eight weeks of Mindfulness-Oriented Recovery Enhancement or a support group. Relative to the support group, Mindfulness-Oriented Recovery Enhancement led to significantly greater reductions in pain severity, functional impairment, opioid craving, and opioid misuse. These clinical outcomes were mediated by effects of Mindfulness-Oriented Recovery Enhancement on a number of neurocognitive mechanisms, including decreased pain attentional bias, reduced opioid cue-reactivity, enhanced natural reward processing, and improved autonomic nervous system regulation during attention to emotional information. Study findings indicate this novel intervention is a promising treatment for co-occurring opioid misuse and chronic pain.