Although research has investigated the association between pathological gaming and academic performance in adolescence, the complexity of the relationship has not been thoroughly examined. This short longitudinal study aimed to investigate the interactions between pathological gaming, academic self-efficacy, academic initiative, and academic performance in an adolescent sample, focusing on sex differences. The participants (N = 2853; 50.1% boys) were students in the second and third years of upper secondary school. Their grade point average (GPA) at graduation the same year was obtained. The moderated mediation structural equation model results showed that academic self-efficacy, directly and indirectly through academic initiative, impacted later GPA. There was no direct effect of pathological gaming on academic initiative or GPA. However, academic self-efficacy moderated the impact of pathological gaming on GPA for boys. In other words, boys with increased pathological gaming tended to achieve poorer grades in school if they experienced a strong academic self-efficacy. This study contributes to the understanding of the complex interplay between sex, pathological gaming, academic self-efficacy, academic initiative, and academic performance. We suggest that future research examines confidence or other relevant factors as explanatory mechanisms in the relationships between pathological gaming, academic self-efficacy, and GPA, particularly in male samples.