Cannabis use in adolescents and young adults is linked with aberrant brain structure, although findings to date are inconsistent. We examined whether aerobic fitness moderated the effects of cannabis on cortical surface structure and whether gender may play a moderating role. Seventy-four adolescents and young adults completed three-weeks of monitored abstinence, aerobic fitness testing, and structural magnetic resonance imaging (sMRI). Whole-sample linear regressions examined the effects of gender, VO2 max, cannabis use, and their interactions on the surface area (SA) and local gyrification index (LGI). Cannabis use was associated with greater cuneus SA. Gender-by-cannabis predicted precuneus and frontal SA, and precentral, supramarginal, and frontal LGI; female cannabis users demonstrated greater LGI, whereas male cannabis users demonstrated decreased LGI compared to non-users. Aerobic fitness was positively associated with various SA and LGI regions. Cannabis-by-aerobic fitness predicted cuneus SA and occipital LGI. These findings demonstrate that aerobic fitness moderates the impact of cannabis on cortical surface structure, and gender differences are evident. These moderating factors may help explain inconsistencies in the literature and warrant further investigation. Present findings and aerobic fitness literature jointly suggest aerobic intervention may be a low-cost avenue for improving cortical surface structure, although the impact may be gender-specific.