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Background: The period of adolescence confers significant vulnerability to mental health problems that may persist into adulthood, causing significant mental health problems to the individual and to society at large However, the majority of what is known about adolescent mental health is rom developed countries. Objective: This study sought to fill the knowledge gap by investigating the influence of peer pressure and substance use on the mental health of in-school adolescents. Methodology: A cross-sectional research design was adopted for this study alongside purposive method for sampling of the participants The sample size was made up of 288 in-school adolescents between the ages of 13 to 22 years, with an average age of 17.02±1.92 drawn from three government schools in Oyo state's capital city. Results: The findings of this study revealed that peer pressure and substance use have a negative impact on mental health. Furthermore, both variables predicted mental health jointly, but only substance use predicted mental health independently. We also discovered no significant gender variation in adolescent mental health. Conclusion: We concluded that substance use is a risk factor for adolescent mental health, as revealed by the outcome of this study. Key Recommendation: As a result, it was recommended that timely and comprehensive mental health interventions should target this population's substance use.