Introduction: This study aimed to examine gender differences in the influence of social, attitudinal, and intrapersonal factors on the onset of smoking, drinking, and the co-occurrence of tobacco and alcohol use among adolescents in South Korea. Methods: Using time-dependent Cox regression, the study analyzed the Korean Youth Panel Study conducted by the Korean National Youth Policy Institute. The study sample was middle-school second-graders (n = 3,188) in South Korea. Results: This study found gender differences between Korean male and female adolescents in models of smoking and alcohol uptake; the co-occurrence model was identical, however. At first, parental supervision, attachment to friends, drinking friends, self-control, and aggression were common factors in the onset of drinking among Korean adolescents. Stress was shown to be significantly correlated with the onset of male adolescent drinking, whereas family income was a significant factor just for females. In the smoking model, attachment to friends, smoking friends, stigma, and self-control were identified as common factors related to the onset of smoking in both male and female adolescents. Attachment to parents was found to be a significant factor for male adolescents and aggression for females. Conclusions: The study findings indicate influences on the commencement of smoking, drinking, and concurrent tobacco and alcohol use among Korean male and female adolescents. Culturally sensitive interventions focusing on common risk factors with several differentiated strategies for both boys and girls should be developed and provided for Korean adolescents.