The aim of the present study was to investigate associations between tooth loss, and oral health literacy, the use of multiple psychoactive substances, and the reason for the last dental appointment in adolescents. A cross‐sectional study was conducted with a representative sample of 746 adolescents aged 15–19 years in Campina Grande, Brazil. Parents/guardians answered a sociodemographic questionnaire. The adolescents answered the Brazilian version of the Rapid Estimate of Adult Literacy in Dentistry (BREALD‐30), the alcohol, smoking, and substance involvement screening test, and an oral health questionnaire from the National Oral Health Survey. The adolescents were then examined by two examiners who had undergone training and calibration exercises for the diagnosis of tooth loss due to caries (K > 0.80). Associations between variables were investigated using robust logistic regression analysis for complex samples (α = 5%). The prevalence of tooth loss was 17.4%. Oral health literacy (OR = 0.93; 95% CI: 0.89–0.97) was inversely associated with tooth loss, while multiple psychoactive substance use (OR = 2.01; 95% CI: 1.09–3.69) and last dental visit for treatment/symptoms (OR = 3.05; 95% CI: 1.73–5.36) were directly associated with tooth loss. Oral health literacy, multiple psychoactive substance use, and reason for last dental appointment exerted an influence on tooth loss among adolescents.