In 2015, psychoactive substance use led to the deaths of 72 young people within a month across Ondo, Edo, and Rivers states in Nigeria, with Ondo being the most affected. The youth attributed these deaths to the wrath of the gods (Malokun) rather than alcohol consumption. This study aims to identify demographic factors influencing youth substance use in Ondo State. Using a cross-sectional, descriptive community study design, 500 participants aged 10 to 24 years were recruited. Data collected through a socio-demographic questionnaire and the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) were analyzed with Statistical Package for Social Science (SPSS) version 16. The findings revealed that alcohol was the most used substance, with a lifetime use prevalence of 69.6%, likely due to the availability and cultural acceptability of local alcoholic products like ogogoro and palm wine. Substance use was found to negatively impact social life. Significant correlates of substance use included gender, age, religion, and father’s relationship. Males had higher lifetime use than females (p = 0.008), and substance use prevalence was higher among late adolescents (p = 0.0034). Christian respondents reported higher lifetime use compared to Muslims (p = 0.010). These results highlight that alcohol is the predominant substance used by young people in Ondo State, with key correlates being male gender, religion, less friendly father relationships, and late adolescence, informing public health strategies to mitigate harmful effects of substance use.