The present study addressed calls for research to identify real-time predictors of prescription drug misuse (Schepis et al., 2020) by testing young adults’ momentary reports of their negative mood and positive mood as predictors of event-level misuse in daily life. We implemented a 28-day ecological momentary assessment (EMA) procedure that collected individuals’ mood and other contextual experiences in moments preceding prescription drug misuse. Consistent with models of problematic substance use as a means to reduce negativity (Khantzian, 1997), results from hierarchical generalized linear modeling indicated within-person links between higher than usual negative mood and greater likelihood of prescription misuse in daily life. Contrary to the hypothesis, misuse was also more likely when preceded by elevated positive mood. We found consistent support for the hypothesized between-person effects, with prescription misuse in daily life associated with higher average levels of negative mood, and lower average levels of positive mood, across the reporting period. We further predicted that individuals reporting greater levels of social anxiety, depression, and externalizing symptoms would evidence stronger links between their momentary negative mood and prescription misuse. Partial support for this moderation hypothesis was found, with the positive within-person link between negative mood and prescription misuse significantly stronger among individuals higher (vs. lower) on social anxiety and depression. Results provide support for intricate connections between young adults’ momentary mood, mental health symptoms, and prescription drug misuse.