Synthetic drug abuse has become an increasingly serious problem among adolescents in Macao, the world’s largest gambling market and the only legal gambling place in China. To counteract this trend, a good understanding of the culturally relevant risk factors for this behavior is required. Based on social learning theory and opportunity perspective of deviance, logistic regression analysis was performed on a probability sample of 8,076 Macao students collected in 2014 to investigate whether delinquent peer association, recreational use of time with friends, attitudes toward drug use, and the availability of synthetic drugs are significant predictors of synthetic drug use among adolescents. The analyses revealed that students who had more drug-using peers, perceived drug use to be less harmful, and had easier access to synthetic drugs were more likely to use drugs. The findings indicate that preventing synthetic drug use among adolescents should target individual risk factors and the availability of drugs.