The objective of this study was to investigate self-medication behavior among Chinese adolescents aged 12–18 years and explore the factors associated with whether adolescents prioritize drug efficacy or safety when engaging in self-medication behavior. In 2021, a questionnaire investigation was conducted in the Chinese mainland using a multi-stage sampling approach. After a statistical description, logistic regression was used to analyze the factors associated with considering drug efficacy and safety. The self-medication rate among Chinese adolescents aged 12–18 years was 96.61%. Of these, 65.84% considered drug safety to be essential, while 58.72% prioritized drug efficacy. Regression analysis showed that individuals with better healthcare were more likely to consider drug efficacy an important factor. Additionally, those with a healthier family lifestyle were more likely to prioritize efficacy. When individuals engage in self-medication, those residing in urban areas and possessing advanced preventive health literacy and ample family health resources tend to prioritize drug safety to a greater extent. Conversely, those with higher monthly household incomes and only children exhibit a decreased inclination towards prioritizing safety during self-medication. Self-medication is a frequently observed practice among Chinese adolescents aged 12–18. Several factors, such as demographic and sociological characteristics, health literacy, and family health status, have been found to be associated with the extent to which adolescents prioritize medication safety and efficacy when engaging in self-medication practices. Higher levels of health literacy and better family health status were positively correlated with considering both the efficacy and safety of drugs as important factors when self-medicating.