Background: Cigarette smoking and alcohol drinking are the most common types of substance use and misuse (SUM) among adolescents. This study aimed to estimate the prevalence and psychosocial factors associated with current cigarette smoking and hazardous alcohol drinking among adolescents in Taiwan. Methods: Data were collected via self-administered questionnaires on computers from students at 14 senior high schools in Taipei, Taiwan. Hierarchical multiple regression strategies were used to determine the risk factors for SUM. Results: A total of 5879 participants were recruited, the majority of whom were female (56.7%). The prevalence rates of current smoking and hazardous alcohol drinking were 3.84% and 7.38%, respectively. Risk factors associated with current smoking were similar to those for hazardous alcohol drinking, including male gender, low school ranking, and depression. In addition, current smoking was associated with increasing age, hazardous alcohol drinking, and fewer parents with whom they can talk, whereas hazardous alcohol drinking was associated with current smoking, not living with both biological parents, and more peers with whom they can talk. Conclusion: The potential coexistence of adolescent SUM and common psychosocial correlates demands an integrated approach. Health professionals should provide corresponding intervention programs and coordinate with parents and teachers to develop an anti-SUM environment, especially for males and high-risk schools. Preventive psychiatric services as an integral part of anti-SUM strategies for adolescents targeting to depression may be useful in reducing the risk.