Abstract Background The nonmedical use of prescribed medicines among adolescents has increased significantly in recent years. Our study was designed to describe the prevalence of the nonmedical use of tranquilizers, sedatives, and sleeping pills (TSSp) among the school-age population residing in Spain from a gender perspective, and to identify factors associated with such use. Methods Nationwide, epidemiological, cross-sectional study on the nonmedical use during the previous 30 days, of TSSp by the Spanish school population. We used individualized secondary data retrieved from the 2004, 2006, 2008, 2010, 2012 and 2014 Spanish state survey on Drug Use in Secondary Education and a total of 179,114 surveys from respondents aged 14 to 18 years. Using logistic multivariate regression models, we estimated the independent effect of each of these variables on the nonmedical use of medicines. Two models were generated- one for females and one for males. Results 2.86% (5116) of the Spanish school population of both sexes made nonmedical use of TSSp. Prevalence was greater among girls than among boys for all the study years. Patterns of nonmedical use among female adolescents were related to alcohol, tobacco and marijuana use. Consumption of illegal psychoactive substances, other than marijuana, was the variable showing the greatest value among male teenagers (aOR 6.21 (95% CI 4.97–7.77). Conclusions The prevalence of the nonmedical use of TSSp is higher in girls than in boys. The influence of legal and illegal psychoactive substances leads to a higher likelihood of nonmedical use of TSSp in high-school students in Spain.