Sexual abuse is a public health problem due to its negative impact on physical and mental health. This study aimed to determine the association between sexual abuse and the use of psychoactive substances among high-school adolescents in Colombia. A cross-sectional analytical study was designed in which tenth and eleventh-grade students were included. Overall, a history of sexual abuse was explored with the Trauma Symptom Checklist, and lifetime substance use was assessed with the United States Centers for Disease Control Youth Risk Behavior Questionnaire. The prevalence of sexual abuse was 17.4%, lifetime alcohol use was 77.4%, cigarette 22.4%, cannabis 11.6%, cocaine 2.7%, and other substances 5.1%. History of sexual abuse was associated with alcohol use (OR = 1.59, 95% CI 1.10-2.30), cigarette (OR = 2.08, 95% CI 1.51-2.85), cannabis (OR = 2.43, 95% CI 1.66-3.56), cocaine (OR = 2.51, 95% CI 1.25-5.04) and use of other substances (OR = 2.33, 95% CI 1.31-4.13). The history of sexual abuse is related to the use of substances in high school adolescents in the Caribbean Region of Colombia. More studies are needed to identify the impact of sexual abuse on short-term and lifelong mental health.