Substance use among school dropouts is a growing global concern that has not been assessed through a meta-analysis. This study aims to provide an overview of the relationship between school dropout and substance use. We searched the PubMed, Embase, Web of Science, Cochrane Library, PsychINFO, ERIC (EBSCO), MEDLINE (EBSCO), and CINAHL (EBSCO) databases for all studies up to April 22, 2024. Articles were pooled using a random effects model to estimate the odds ratios and 95% confidence intervals (CIs). The results revealed that the risk of tobacco use among dropouts was 1.92 times higher compared to nonschool dropouts (1.92 [95% CI: 1.32, 2.79]), and 1.91 times higher for using drugs (1.91 [95% CI: 1.63, 2.23]). Subgroup analysis indicated that high school dropouts with a General Educational Development credential did not alleviate substance use (1.98 [95% CI: 1.57, 2.51]). The pooled effect of injecting drug use was higher than other drug use among dropouts (2.22 [95% CI: 1.85, 2.66]). Schools should provide timely attention to students at risk of dropping out, offer academic support and mental health services, and work closely with parents to mitigate the incidence of student dropout and substance use.