Based on Social Cognitive Theory (SCT) and the Risk Perception Attitude (RPA) Framework, this study used a survey to examine various factors affecting the risk perception and behavior related to prescription opioid drug (POD) misuse among college students. The results showed that trait reactance, helicopter parenting, and peer pressure were negatively associated with risk perception and positively correlated with POD misuse. Self-efficacy, on the other hand, was positively linked with risk perception and negatively connected with POD misuse. Risk perception was negatively correlated with POD misuse. In addition, self-efficacy moderated the relationship between risk perception and the misuse. This study extends the purview of both SCT and the RPA by testing their central predictions among a sample of a demographic group most vulnerable to the opioid epidemic. It also sheds light on the development of more effective prevention and intervention efforts to counter this burgeoning crisis. Limitations and directions for future research were outlined.