This study evaluated the influence of Oral Health-Related Quality of Life (OHRQoL) on the consumption of alcohol and cigarette use in adolescents. This prospective cohort began in 2012 (T1) with an initial random sample of 1134 12-year-old adolescents followed for 6 years in Santa Maria, southern Brazil. The present study comprised data from the two cohort reassessments that took place in 2014 (T2) and 2018 (T3). OHRQoL was measured with the Brazilian short version of the Child Perceptions Questionnaire (CPQ11-14) at T2. Socioeconomic, demographic, and oral health measures were also collected during this period. Alcohol and cigarette consumption (regular use) in the past 30 days was evaluated at T3 through questions in the of the National School Health Survey (PeNSE) questionnaire. A multilevel Poisson regression model was used to evaluate the influence of predictor variables on substance use. Of the 770 adolescents at T2, 575 and 576 adolescents were reassessed at T3 for alcohol and cigarette consumption, respectively. Adolescents with higher overall CPQ11-14 scores were at higher risk for regular consumption of alcohol (IRR 1.01; 95% CI 1.01-1.02) and cigarette (IRR 1.04; 95% CI 1.03-1.05). Non-white adolescents with low socioeconomic status, untreated dental caries, and who had not been to the dentist (last 6 months) were also associated with increased regular consumption of licit substances. Adolescents with worse OHRQoL presented a higher consumption of alcohol and cigarette. These findings are useful for planning public health strategies to improve adolescent OHRQoL and reduce the harmful substance use.