Background: It is projected that low and middle-income countries will bear a major burden of tobacco related morbidity and mortality, yet, only limited information is available on the determinants of smoking initiation among youth in Africa. This study aimed to assess the determinants of smoking initiation and susceptibility to future smoking among a population of high school school students in Lagos, Nigeria. Materials and Methods: Baseline data from an intervention study designed to assess the effect of an anti-smoking awareness program on the knowledge, attitudes and practices of adolescents was analyzed. The survey was carried out in six randomly selected public and private secondary schools in local government areas in Lagos state, Nigeria. A total of 973 students completed self-administered questionnaires on smoking initiation, health related knowledge and attitudes towards smoking, susceptibility to future smoking and other factors associated with smoking. Results: Of the respondents, 9.7% had initiated smoking tobacco products with the predominant form being cigarettes (7.3%). Males (OR: 2.77, 95%CI: 1.65-4.66) and those with more pro-smoking attitudes (OR: 1.44, 95%CI: 1.34-1.54) were more likely to have initiated smoking. Those with parents and friends who are smokers were 3.47 (95%CI: 1.50-8.05) and 2.26 (95%CI: 1.27-4.01) times more likely to have initiated smoking. Non-smoking students, in privately owned schools (OR: 5.08), with friends who smoke (5.09), with lower knowledge (OR: 0.87) and more pro-smoking attitudes (OR 1.13) were more susceptible to future smoking. In addition, respondents who had been sent to purchase cigarettes by an older adult (OR: 3.68) were also more susceptible to future smoking. Conclusions: Being male and having parents who smoke are predictors of smoking initiation among these students. Consistent with findings in other countries, peers not only influence smoking initiation but also influence smoking susceptibility among youth in this African setting. Prevention programs designed to reduce tobacco use among in-school youth should take these factors into consideration. In line with the recommendations of article 16 of the WHO FCTC, efforts to enforce the ban on the sales of cigarettes to minors should be also emphasised.