This meta-analysis synthesized 97 effect sizes extracted from 37 intervention studies for students with reading difficulties (RDs) in Grades 6 to 12 published between 1982 and 2021 to identify the overall impact of reading interventions and the moderating effects of intervention characteristics and study design characteristics. Random-effects robust variance estimation (RVE) was used to account for dependencies within studies. Overall, interventions designed to improve reading comprehension outcomes for adolescents with RDs were effective (g = 0.63). Meta-regression analyses identified several significant moderators that were associated with intervention efficacy, such as text content, duration of intervention, agent of intervention, status of student, type of dependent measure, and study quality. We provide study limitations as well as implications for research and practice.