This systematic review evaluates single-case research design studies investigating applied behavior analytic (ABA) interventions for people with Down syndrome (DS). One hundred twenty-five studies examining the efficacy of ABA interventions on increasing skills and/or decreasing challenging behaviors met inclusion criteria. The What Works Clearinghouse standards and Risk of Bias in N-of-1 Trials scale were used to analyze methodological characteristics, and Tau-U effect sizes were calculated. Results suggest the use of ABA-based interventions are promising for behavior change in people with DS. Thirty-six high-quality studies were identified and demonstrated a medium overall effect. A range of outcomes was targeted, primarily involving communication and challenging behavior. These outcomes will guide future research on ABA interventions and DS.