Purpose: Alcohol can have serious side effects alone and can enhance the side effects of prescription opioids in unpredictable and dangerous ways. This study aims to identify risk factors for simultaneous use of alcohol and prescription opioids among young adults. Methods: Demographic characteristics, substance use, mental well-being, other substance-related factors, and simultaneous use of alcohol and prescription opioids were utilized to run multiple logistic regression analysis ( N = 1751; aged 18–25). Results: Mental well-being ( OR = 0.971, p = .003) and education level ( OR = 0.383, p < .001) were associated with a lower likelihood of simultaneous use. Knowing someone who had a fatal overdose ( OR = 2.443, p < .001), binge drinking ( OR = 1.065, p = .012), and older age ( OR = 1.250, p < .001) were associated with a greater likelihood of simultaneous use. Conclusion: The risk and protective factors identified in the current study point to specific areas for intervention to reduce simultaneous use. Further efforts are needed to minimize the increasing polysubstance-involved overdose mortality among young adults.