Background: Substance abuse among youths is fast becoming a global Public Health concern. Objectives: This study assessed the prevalence and factors associated with substance abuse in selected public schools in Ogbomoso, South-West Nigeria. Methods: Cross-sectional study design and multi-stage sampling method were utilized among 249 study participants who gave informed consent/assent. Data were collected using facilitated, self-administered questionnaire.Descriptive and inferential statistics using the Chi-Square test were carried out at p<0.05. Results: The mean age of our respondents was 16.3±2SD; 40.0% of them had positive attitude to substance abuse while 21.7% had ever consumed alcoholic drinks. In all, 31(26.3%) of the respondents satisfied the criteria used in defining substance abuse.Tramadol was the most commonly abused substance apart from alcohol; reported by 39.0% of the substance abusers. Most (35.5%) of the substance abusers did so believing it could enhance their academic performance. The proportion of respondents who were substance abusers was significantly higher among students who had not received any formal lectures on the subject at school compared to those who had.(47.5% vs 29.7% ;p=0.023). Conclusion: Our findings underscore an urgent need to intensify awareness against substance abuse among secondary school students in Nigeria.