Objective To examine the longitudinal relationship between neuropsychological functioning and internalizing symptoms, as mediated by social competence in youth with spina bifida (SB). Methods A total of 111 youth (aged 8–15 years, M = 11.37) with SB, their parents, and teachers completed questionnaires regarding attention, social competence, and internalizing symptoms. Youth also completed a battery of neuropsychological tests. Results An indirect-only mediation model revealed that social competence mediated the relation between neuropsychological functioning and subsequent levels of teacher-reported internalizing symptoms, but not parent or youth report of internalizing symptoms. Specifically, better neuropsychological functioning was associated with better social competence, which, in turn, predicted fewer internalizing symptoms 2 years later. Conclusions Youth with SB with lower levels of neuropsychological functioning may be at risk for poorer social competence and, as a result, greater internalizing symptoms. Interventions that promote social competence, while being sensitive to cognitive capacities, could potentially alleviate or prevent internalizing symptoms in these youth.