Purpose A rapid increase of recreational nitrous oxide use (i.e. laughing gas, N2O) has been reported in several countries, while it has received limited attention in scientific research. We aimed to study the association of socio-demographic characteristics, mental well-being, sickness absence, truancy, and substance use with the frequency of lifetime nitrous oxide use among adolescents. Methods We used self-reported questionnaire data of adolescents (N = 555) attending secondary schools to cross-sectionally assess the frequency of nitrous oxide use and potential factors associated with nitrous oxide use, such as gender, mental well-being, and binge drinking. Ordinal logistic regression models were applied with lifetime nitrous oxide use (never, once, ≥ two times) as the outcome variable. Results Adolescents were on average 15.6 years old (SD = 0.83, range 14–18), 47.0% were female. In total, 86 (15.6%) adolescents had used nitrous oxide at least once in their life. In the multivariable ordinal regression model, the risk of having a higher category of lifetime nitrous oxide use was associated with a non-Dutch ethnic background (OR = 2.10, 95% CI 1.22; 3.61), attending pre-vocational education (OR = 1.88, 95% CI 1.06; 3.34), a higher score on the scale of externalizing problems (OR = 1.10, 95% CI 1.01; 1.20), binge drinking twice or more in the past four weeks (OR = 2.49, 95% CI 1.25; 4.94), and cannabis use (OR = 1.98, 95% CI 1.03; 3.79). Conclusions Youth Health Care professionals should be aware of nitrous oxide use in adolescents, especially among adolescents with a non-Dutch ethnic background, lower education levels, externalizing problems, frequent binge drinking, and cannabis use.