A meta-analysis of single-case design research was conducted to evaluate the effectiveness of mathematics interventions for elementary grade (K-5) students with mathematics difficulties (MD) and mathematics learning disabilities (LD). The study examined whether intervention effectiveness varied as a function of participant characteristics (i.e., grade level, MD/LD status), intervention characteristics (i.e., intervention type, intervention implementer, intervention duration, intervention group size, mathematics domain), and study quality (i.e., evidence of a functional relation). Results included 20 studies published from 2009 to 2021, with a total of 31 effect size estimates. The overall mean effect size estimate was 0.91 (p < .01), indicating significant positive outcomes for students with MD and LD after receiving mathematics interventions. Moderator analyses indicated that grade level and intervention type moderated treatment effects, such that students in Grade 3 showed higher treatment effects than students in Grade 2, and interventions that used explicit instruction yielded the highest effect sizes compared to interventions that used schema-based instruction, cognitive strategy instruction, and concrete representational abstract (CRA) instruction. Disability status, intervention duration, intervention group size, mathematics domain, intervention implementer, and study quality did not moderate intervention effects. However, findings from the moderator analyses should be interpreted with caution given the small number of studies within various categories. The present study provides further evidence regarding the effectiveness of mathematics interventions for students with MD and LD when using single-case research design. Limitations, directions for future research, and implications for practice are discussed.