This study examines academic self-efficacy and gender as predictors of internalizing and externalizing behaviors in adolescence. In addition, the role of gender was considered as a moderator in the relationship between academic self-efficacy and internalizing/externalizing difficulties. Participants were 4,318 predominantly African American, low-income high school students who completed self-report measures on the constructs of interest. Academic self-efficacy and gender were both significant predictors of risk for internalizing problems, whereas only academic self-efficacy predicted risk for externalizing (hyperactivity/distractibility) problems. Gender did not predict externalizing difficulties, nor did gender serve as a moderator in any analysis. Implications include focusing on academic self-efficacy in the development of strategies for prevention and intervention of internalizing and externalizing problems.