This study conducted a meta-analysis and methodological review to examine the relationship between sexual orientation and adolescent substance use. The primary aims were to assess the risk of substance use among lesbian, gay, and bisexual (LGB) adolescents compared to heterosexual youth and to critique the methodological characteristics of existing literature. Eighteen studies were included, and data analysis followed expert guidelines using NIH-sponsored meta-analysis software. The results showed that LGB adolescents reported significantly higher rates of substance use compared to heterosexual youth (odds ratio = 2.89, Cohen’s d = 0.59). Effect sizes varied by gender, bisexuality status, sexual orientation definition, and recruitment source. The study found that the odds of substance use for LGB youth were 190% higher than for heterosexual youth, with even higher rates for bisexual youth (340%) and females (400%). The meta-analysis also identified moderators such as the definition of sexual orientation, recruitment source, gender, and country of origin. However, the study noted methodological limitations, including the lack of testing for mediation and moderation, and the need for more research to understand the underlying mechanisms and long-term outcomes. The findings highlight the need for targeted interventions and support for LGB youth to address their higher risk of substance use.This study conducted a meta-analysis and methodological review to examine the relationship between sexual orientation and adolescent substance use. The primary aims were to assess the risk of substance use among lesbian, gay, and bisexual (LGB) adolescents compared to heterosexual youth and to critique the methodological characteristics of existing literature. Eighteen studies were included, and data analysis followed expert guidelines using NIH-sponsored meta-analysis software. The results showed that LGB adolescents reported significantly higher rates of substance use compared to heterosexual youth (odds ratio = 2.89, Cohen’s d = 0.59). Effect sizes varied by gender, bisexuality status, sexual orientation definition, and recruitment source. The study found that the odds of substance use for LGB youth were 190% higher than for heterosexual youth, with even higher rates for bisexual youth (340%) and females (400%). The meta-analysis also identified moderators such as the definition of sexual orientation, recruitment source, gender, and country of origin. However, the study noted methodological limitations, including the lack of testing for mediation and moderation, and the need for more research to understand the underlying mechanisms and long-term outcomes. The findings highlight the need for targeted interventions and support for LGB youth to address their higher risk of substance use.