Purpose: This study aimed to identify the cross-national estimates of substance use, explore problematic substance use patterns among adolescents across countries and over time, and examine the relationship of individual characteristics on substance use patterns. Methods: This study employed a time-series secondary data analysis spanning from 2014 to 2021 across four countries (United States, Canada, England, and South Korea). We analyzed the usage of five substances (alcohol, binge drinking, cigarettes, electronic cigarettes, and illicit drugs) alongside demographic characteristics. A descriptive analysis was performed to identify estimates of substance use across countries. Latent class analysis was employed to examine adolescents’ substance use patterns across time and countries. A multinomial logistic regression model was fit to assess the relationship between latent class and demographic characteristics. Results: Adolescents in the United States and Canada had the highest substance use, while Korean adolescents had the lowest, particularly concerning drugs. Latent class analysis revealed two classes (light-user and heavy-user), with the addition of a third class (moderate-user) in some instances. The substance use patterns, while differing significantly among nations, exhibited consistency over time. During COVID-19, a decrease in heavy-substance users was observed across countries. Male or older participants were more likely to belong to the heavy-user class. Conclusion This research offers valuable insights into the variations in substance use patterns between nations and over time. A tailored approach is essential to prevent adolescents from becoming heavy-substance users. This approach should consider country regulations and demographics for a targeted and comprehensive preventive strategy.