Abstract Background Non-medical use of prescription drugs has become a global concern in recent decades. This study aimed to explore trends in non-medical tranquilizers and sedatives use (NTSU) among adolescents in Estonia from 2003 to 2019. Methods Utilizing data from the cross-sectional European School Survey Project on Alcohol and Other Drugs (ESPAD) conducted in 2003-2019, study included 15-16-year-old Estonian schoolchildren (n = 11,328; 48.6% boys). Cochran-Armitage test was employed to assess changes in NTSU trends, with statistical significance set at p < 0.05. Prevalence rates and 95% CIs used as outcome measures. Results From 2003 to 2019, the lifetime prevalence of NTSU significantly increased for both genders, with girls consistently showing higher rates. Among boys, NTSU rose from 5.0% (95% CI 3.8-6.5) to 11.3% (95% CI 9.6-13.3), particularly among those reporting NTSU 1-2 times, from 3.0% (95% CI 2.1-4.2) to 8.2% (95% CI 6.7-9.9), p < 0.001. Similarly, for girls, NTSU rose from 12.6% (95% CI 10.7-14.7) to 17.5% (95% CI 15.4-19.7), p < 0.001. There was an increase among girls reporting NTSU 1-2 times from 7.5% (95% CI 6.0-9.2) to 10.6% (95% CI 9.0-12.4), p < 0.001, and those reporting NTSU three or more times, from 5.1% (95% CI 3.9-6.6) to 6.9% (95% CI 5.6-8.4), p = 0.017. Among boys reporting medical tranquilizers and sedatives use (MTSU), NTSU rose from 21.1% (95% CI 13.9 to 30.0) in 2003 to 41.4% (95% CI 32.3 to 50.9) in 2019, p = 0.006. However, there was no statistically significant change in NTSU among girls reporting MTSU, remaining at 44.1% (95% CI 36.0 to 52.4) in 2019, p = 0.951. Conclusions Study reveals a significant increase in lifetime NTSU from 2003 to 2019, with girls consistently showing higher prevalence. Targeted interventions are needed to address adolescent non-medical prescription drug use, particularly among girls. Moreover, substantial NTSU among those reporting MTSU highlights the need to monitor and address non-medical usage in this subgroup. Key messages • Estonian adolescent non-medical tranquilizers and sedatives use surged from 2003 to 2019, particularly among girls, highlighting the need for targeted interventions. • The high prevalence of non-medical tranquilizer and sedative use among those reporting medical tranquilizer and sedative use underscores the necessity for vigilant monitoring.