The increasing co-use of e-cigarette and cannabis among youth has become a public health challenge. The present analyses aimed to identify prevalence and correlates of past-month co-use of e-cigarettes and cannabis among adolescents with and without prior tobacco use. For this panel study, 5 years of cross-sectional data (2014–2018) were used from 8th, 10th-, and 12th-grade adolescents in the Monitoring the Future study, a nationally representative survey of U.S. students. We examined prevalence and correlates of e-cigarettes and cannabis co-use among adolescents who had ever used tobacco (n = 15,136) and among those who had never used tobacco (n = 56,525). Adolescents who had ever used tobacco showed significantly higher rates of e-cigarettes and cannabis co-use compared to adolescents who had never used tobacco (17.1% vs. 2.2%, p < 0.01). Results from adjusted multinomial regression models showed that overall, Black and Hispanic adolescents tobacco users were less likely than Whites to co-use e-cigarettes and cannabis. Black adolescents who had used tobacco previously were more likely than Whites to have used cannabis exclusively. Black and Hispanic tobacco-naïve adolescents were more likely than Whites to have used cannabis exclusively, while Black tobacco-naïve adolescents were less likely to use e-cigarettes exclusively or co-use e-cigarettes and cannabis. Overall, males and twelve graders were more likely than males and eight graders to use or co-use cannabis or e-cigarettes, respectively. Among lifetime tobacco users, higher levels of parental education were associated with co-use of cannabis and e-cigarettes. Racial/ethnic-specific patterns of e-cigarette and cannabis co-use depends on adolescents’ prior experience with tobacco. The higher rates of use and co-use of e-cigarettes and cannabis among prior tobacco users suggest that targeted interventions are needed for this group. Identified socio-demographic groups at higher risk of co-use of e-cigarettes and cannabis need to be further studied.