IntroductionSubstance use amongst adolescents remains a global public health challenge. The potential negative health outcomes of substance use suggest the need to understand the pattern of use and the associated factors among adolescents. This study aimed to describe the prevalence of substance use, SUDs, and PD and the associated factors in adolescent learners at public schools in Gaborone, Botswana.MethodsA cross-sectional study was conducted at 13 public secondary schools in Gaborone among 742 students. Assessment tools included the World Health Organization drug questionnaire, DSM-5 interview for SUD, and the General Health Questionnaire-12.ResultsThe mean age (SD) of the participants was 15.26 (1.57) years, and there were more females (55.5%). Over two-fifths (44.6%) of learners reported psychoactive substance use in the past 12 months, and 31.5% meeting DSM 5 criteria for a SUD. Alcohol was the most used psychoactive substance (25.1%). Male gender (AOR = 1.94; 95% CI: 1.26–2.995), having a friend (AOR = 4.27; 95% CI: 2.68–6.78), or father (AOR = 1.87; 95% CI: 1.14–3.04), who uses substance, and higher levels of PD (AOR = 1.09; 95% CI: 1.03–1.17) remained significantly associated with SUD. Regular participation in religious activities negatively correlated with SUD (AOR = 0.61; 95% CI: 0.38–0.96).ConclusionThe high prevalence of substance use and SUDs among in-school adolescents is concerning. Substance use programs need to include family-focused and religious-based therapy and youth empowerment in developing positive peer relationships. Also, they should be integrated with mental health screening to assess comorbid PD.