Background: Psychoactive substance use causes significant social burden and is linked with a range of adverse outcomes. The critical age of onset is usually around adolescence, with affected youth experiencing higher prevalence of psychosocial problems compared with the general adolescent population. This study determined the prevalence and examined the association between psychoactive substance use and psychiatric disorders among adolescents in Ogbomoso, Nigeria. Methods: This study was an observational descriptive cross-sectional survey conducted among 394 adolescent students from five selected secondary schools in a rural area. A sociodemographic questionnaire was administered to all participants while the ASSIST and K-SADS instruments were used to assess substance and psychiatry disorder respectively. Subjects with scores above the screening cut-off point were subsequently interviewed. Data collected were analyzed using SPSS version 21. Results: Prevalence of lifetime substance use was 27.3% (n = 96). All the different types of psychoactive substances evaluated in the study were used by the respondents. The most predominant substance used was alcohol (19.9%), with 2.3%, and 0.6% of the respondents reporting monthly and weekly use respectively. There was a statistically significant association between family history of mental illness and lifetime use of substances among respondents, p-value = 0.007. The prevalence of psychiatric disorders was 17.6%. The prevalence of Depression and mania constituted 62.1% of the psychiatric disorders recorded among these respondents. There was no significant association between psychoactive substance use and psychiatric disorders among respondents in the study population. Conclusion: Psychoactive substance use was common among rural secondary school students with 1 in every of 4 having experienced it. Nearly one in five also had a psychiatric disorder but no significant association was found between the two.