Background Multidimensional family therapy (MDFT) is a well‐established treatment for adolescents showing both substance abuse and/or antisocial behavior. Method The effectiveness of MDFT in reducing adolescents’ substance abuse, delinquency, externalizing and internalizing psychopathology, and family malfunctioning was examined by means of a (three‐level) meta‐analysis, summarizing 61 effect sizes from 19 manuscripts (N = 1,488 participants). Results Compared with other therapies, the overall effect size of MDFT was significant, albeit small in magnitude (d = 0.24, p < .001), and similar across intervention outcome categories. Moderator analysis revealed that adolescents with high severity problems, including severe substance abuse and disruptive behavior disorder, benefited more from MDFT than adolescents with less severe conditions. Conclusions It can be concluded that MDFT is effective for adolescents with substance abuse, delinquency, and comorbid behavior problems. Subsequently, it is important to match specific characteristics of the adolescents, such as extent of impairment, with MDFT.