ObjectivesThis study aimed to (1) to describe trends of tranquilliser and sedative (TS) misuse in Estonia during 2003–2019 and (2) to analyse the associations between TS misuse and explanatory factors (perceived access to TS, medical use of TS, family-related, friends-related, school-related factors, risk behaviour and leisure time physical activity).DesignA cross-sectional study.SettingData were collected from the European School Survey Project on Alcohol and Other Drugs (ESPAD) from 2003 to 2019 in Estonia.ParticipantsEstonian schoolchildren aged 15–16 years old (n=11 328), 48.6% were boys.Outcome measuresPrevalence, crude and adjusted ORs with 95% CIs for TS misuse.ResultsThe prevalence of lifetime TS misuse significantly increased from 2003 (5.0% of boys and 12.6% of girls) to 2019 (11.3% and 17.5%, respectively) (p<0.001). Among boys, TS misuse increased significantly among those reporting medical use of TS from 21.1% to 41.4% in 2003–2019 (p=0.006). Medical use of TS multiplied the odds of misuse by 6.89 (95% CI 5.15 to 9.24) for boys and by 4.53 (95% CI 3.58 to 5.73) for girls. Perceived easy access to TS increased the odds of misuse by 6.57 (95% CI 4.13 to 10.46) times for boys and by 4.66 (95% CI 3.25 to 6.70) times for girls. Having many friends who misuse TS increased the odds of misuse by 3.27 (95% CI 2.16 to 4.95) times for boys and by 5.07 (95% CI 3.79 to 6.77) times for girls. Furthermore, higher odds of TS misuse were observed among adolescents who smoked cigarettes and engaged in less sports.ConclusionsTS misuse prevalence among Estonian adolescents increased significantly from 2003 to 2019. Misuse was strongly associated with medical use, perceived easy access and friends’ TS misuse. These findings emphasise the need for targeted prevention strategies, including improving prescription practices, limiting TS access and promoting healthy behaviours and positive peer relationships among adolescents.