BackgroundThe issue of problematic Internet use (PIU) amongst college students is emerging as a major concern for mental health. Factors such as health literacy, subjective well-being and the extent of social support may be critical in preventing PIU. However, the complex relationship between these factors has not been extensively explored in research. MethodsA national cross-sectional study based on multistage random sampling was conducted in China in 2022. The subjects for this study were 7669 college students who completed a set of questionnaires assessing their health literacy, subjective well-being, PIU and social support. A structural equation model (SEM) was utilised for exploring the mediating effect of subjective well-being, and the PROCESS macro was used to test the moderating effect of social support. ResultsAfter controlling for demographic factors, a significantly negative correlation was found between health literacy and PIU, and subjective well-being partially mediated this relationship. In addition, social support was negatively related to PIU and could moderate the relationship between health literacy and subjective well-being and between subjective well-being and PIU. LimitationsThis is a cross-sectional study, and the results cannot inform the causality between these variables. ConclusionResults revealed that the relationship between health literacy and PIU was partially mediated by subjective well-being in college students. The correlation between health literacy and subjective well-being and between subjective well-being and PIU were moderated by social support. Thus, future interventions for college students' PIU should be facilitated by improving health literacy, subjective well-being and social support.