Background: Substance use is prevalent and is associated with academic performance among adolescents. Few studies have examined the association between abstinence from all substances and academic achievement. Methods: Data from a nationally representative sample of 9578 12th graders from the 2015 Monitoring the Future survey were analyzed to examine relationships between abstinence from substance use and 4 academic variables: skipping school, grades, academic self-efficacy, and emotional academic engagement. Participants were categorized as lifetime non-users, former users, and past-year users based on the use of 14 substances. Results: Approximately one-fourth of participants had never used cigarettes, alcohol, or other drugs during their lifetime, and 8%[subscript wt] used at least one substance during their lifetime but not during the past year. Adjusting for demographic variables, past-year substance users had 2.71 greater odds of skipping school during the past month than lifetime non-users and 1.74 greater odds of having low grades. Lifetime non-users reported greater academic self-efficacy and emotional academic engagement than past-year users. Conclusions: Many 12th graders have abstained from all substance use during their lifetime, and these adolescents experience better academic outcomes than their substance-using peers. Substance use prevention programs should be evaluated as a way to promote academic achievement.