Some of the perceived consequences of substance use are reflected in poor academic outcomes. In the current study, the relationship between adolescent substance use and academic outcomes was investigated using a large national database of middle school and high school students (Monitoring the Future, 2008). It was hypothesized that (1) early onset users compared to both late onset users and non-substance users would be at greater risk of poor academic outcomes, (2) frequency of substance use would moderate the relationship between onset age and academic outcomes, and (3) peer influence would intensify and parental involvement would attenuate the negative relationship between nature of substance use and academic outcomes. The results suggested three primary findings that generally supported these hypotheses. First, the nature of substance use was significantly associated with poor academic outcomes—students who engaged in substance use (regardless of onset age and frequency of use) were more likely to report poor academic interest, academic effort, and academic achievement than non-users. Second, the number of substance-using peers related negatively with academic outcomes, and to some extent, might be more detrimental than the nature of substance use. Finally, parental involvement was associated with favorable academic outcomes and appeared to play a protective role in attenuating adolescent substance-use and association with substance-using peers. In summary, these results suggested that multiple mechanisms are at play in explaining adolescent substance use and academic outcomes. This calls for a broader policy that aims beyond just the nature of substance use, but one that also incorporates contextual and environmental factors. Most notably, the current study supports increased efforts to encourage better parental practices and involvement in combating substance use and enhancing academic outcomes among American students.