Death and morbidity associated with substance use have risen continuously over the last few decades, increasing the need for rigorous examination of promising programs. Interventions attempting to change multiple behaviors have been designed to address interconnected problems such as use of both alcohol and drugs. This meta-analysis aimed to examine the efficacy of multibehavior interventions to curb nonmedical substance use in relation to the theoretical relation among different substance use behaviors. Specifically, our synthesis aimed to estimate the optimal number of recommendations for intervention efficacy and evaluate the impact of different combinations of recommendations on intervention efficacy. A synthesis of multibehavior interventions addressing nonmedical substance use was conducted to measure behavioral changes between the pretest and the follow-up. These changes were then compared across different numbers of recommendations. Sixty-nine reports and 233 effect sizes (k of conditions = 155, n = 28,295) were included. A positive linear relation was found between the number of targeted behaviors and intervention efficacy, which was stronger for drug use than alcohol use. Furthermore, recommendations on drug use worked better when paired with recommendations targeting other behaviors, whereas recommendations on alcohol use worked more independently. Lastly, multibehavior interventions were especially efficacious when delivered by experts. Overall, our synthesis indicated that targeting multiple substances is beneficial for changing drug use outcomes, but less so for alcohol use outcomes. Therefore, in the current substance use epidemic, innovative multibehavior programs appear to hold promise, especially to combat nonmedical drug use. (PsycInfo Database Record (c) 2020 APA, all rights reserved).