Purpose Rural communities are currently being impacted by a nationwide epidemic of prescription opioid misuse. Rural adolescent substance users may be at substantial risk for later addiction to these and other drugs. Methods This study uses Latent Class Analysis to identify subtypes of polysubstance users among a sample of 7,074 rural adolescents. Separate models were estimated for middle‐ and high‐school youth. Predictive validity was estimated using cumulative ordinal logistic regression of the classes on a set of youth and family characteristics. Findings We identified a 4‐class solution for both middle‐ and high‐school students marked by initiation of an increasing number of substances used at greater frequency. These classes included Substance Nonusers, Primarily Alcohol Users, Initiators‐Low Frequency Users, and Initiators‐Moderate‐to‐High Lifetime Frequency Users. About 6%‐10% of youth reported using prescription drugs at least once, and in the moderate‐to‐high frequency class, middle‐school youth were more likely to use prescription drugs and inhalants compared to high‐school youth in the same class. The 4 classes were associated with race/ethnicity, and in high school with receiving free/reduced price lunch. Conclusion In general, younger adolescents have lower overall use rates, but within certain classes identified by this analysis, the observed pattern suggests that younger cohorts are turning to prescription drugs and inhalants. These findings support the implementation of universal substance use prevention programs, targeted programs for youth experiencing risk factors associated with substance use, and improved rural substance abuse treatment options.