Mathematics difficulties (MD) affect about 20% of the students in German schools. Almost half of them also exhibit emotional and behavioral difficulties (EBD). While a growing number of mathematics interventions target children with MD separately, there is a lack of evidence for the effectiveness of these interventions for children with combined MD and EBD. This study aims to investigate the differential effects of an evidence-based mathematics intervention on children with and without EBD. This single-case study examined 11 children with internalizing and externalizing EBDs from grades 3 and 4 using a staggered AB-Design. A computer-based mathematics intervention was provided for 5 weeks, during which the mathematical performance of the students was measured using a learning progress assessment in A- and B-phases. Data were analyzed using (a) overlap indices, (b) piecewise linear regression (PLM) models for each student, and (c) a multilevel PLM across all children. The results suggest different effectiveness for children with and without EBD, indicating a small direct influence of the severity of the EBD. Thus, the effectiveness of mathematics interventions might not be generalizable for children with combined EBD and MD. Further research is necessary to better understand the differential effectiveness of mathematics interventions for these children.