Depression, a prognostic factor for prescription opioid misuse commonly occurs in people with chronic non-cancer pain (CNCP). However, the mechanisms linking depression and prescription opioid misuse remain unclear. This study examined the potential mediating role of pain catastrophizing in the association between depressive symptoms and prescription opioid misuse risk, and impulsivity traits as possible moderators of these relationships. Individuals (N = 198; 77% women) with CNCP using prescription opioids participated in a cross-sectional online survey with validated measures of depression, pain catastrophizing, rash impulsiveness, reward drive, anxiety, pain severity and prescription opioid misuse. Meditation analyses with percentile-based bootstrapping examined pathways to prescription opioid use, controlling for age, sex, pain severity, and anxiety symptoms. Partial moderated mediation of the indirect effect of depressive symptoms on prescription opioid misuse risk through pain catastrophizing by rash impulsiveness and reward drive were estimated. Pain catastrophizing mediated depressive symptoms and prescription opioid misuse risk. Indirect effects were stronger when moderate to high levels of reward drive were included in the model. Findings suggest the risk of prescription opioid misuse in those experiencing depressive symptoms and pain catastrophizing is particularly higher for those higher in reward drive. Treatments targeting these mechanisms may reduce opioid misuse risk. Perspective: This article identifies reward drive as a potentially important factor increasing the effects of depression-related cognitive mechanisms on risk of prescription opioid misuse in those with CNCP. These findings could assist in personalizing clinical CNCP management to reduce the risks associated with opioid misuse.