A rapid rise in the number of tobacco users in Saudi Arabia has occurred in the past decade, particularly among the youth. This study identified socio-cultural determinants of tobacco use and explored possible approaches to prevent adolescents' tobacco use in Saudi Arabia. A cross-sectional survey was administered using a self-administered questionnaire for collecting information on risk and protective factors for tobacco use among middle school students. School selection was stratified by region, gender, and type (public or private). Of 1,186 7-9th grade students, 1,019 questionnaires were analyzed. Risk factors affecting tobacco use included all important others' perceptions; mother, sister, friend, teacher and important person's tobacco use; pressure to use tobacco from brother, sister, friend and important persons; easy access to tobacco and frequent skipping of classes. Protective factors for tobacco use included family's perception; friend, teacher and important person's tobacco use; parents' help; support from family, friends, and teachers; accessibility to tobacco; school performance and family income, father's education, and district of residence. The findings of this study show clear gender differences in social influences and attitudes towards tobacco use. Religious beliefs and access to tobacco products were significantly associated with attitudes towards tobacco use and future intention of use. Developing and implementing effective gender specific school-based tobacco prevention programs, strict reinforcement of tobacco control policies, and a focus on the overall social context of tobacco use are crucial for developing successful long-term tobacco prevention programs for adolescents.