Current dietary supplement (DS) use among Saudi school students is not well described. In this study, we aim to investigate the prevalence and predictors of DS use among adolescents. This cross-sectional study collected data via self-administered questionnaire from 1221 students (12 to 18 years). The overall prevalence of DS use was 26.2%, significantly higher in females than males (33% vs. 17.9%, p < 0.001). High proportion of female DS users demonstrated normal BMI than males (84% vs. 56.5%, p < 0.001). High percentage of male DS users were engaged in vigorous and/or high physical activity (PA) levels than female DS users (58.2% vs. 43%, p = 0.022; and 57.1% vs. 20.7%, p < 0.001, respectively). The main reasons for DS use among females were vitamin deficiency (63.3%), hair condition (37.6%) and nail health (23.5%) while in males, the main reasons were vitamin deficiency (58.4%) and body building (34.4%). The predictors of DS use in Saudi adolescents included being female, having high family income and being physically active. In conclusion, the overall prevalence and preference of DS use, though low among Saudi adolescents, was driven mostly by gender, physical activity levels and socioeconomic factors like family income. DS use guidelines and counselling among Saudi adolescents are warranted to improve public health.