Aim <p>Mental health among middle-aged and older women is an important public health concern. Physical health is closely associated with psychological well-being, yet the roles of social and cognitive resources in shaping this relationship remain insufficiently understood. In particular, how health literacy and family support modulate the link between physical and mental health has received limited empirical attention. This study aims to investigate the role of family support and health literacy in relation to physical and mental health status in middle-aged and older women.</p> Subject and methods <p>A cross-sectional study of 3459 middle-aged and older women examined reported health and well-being using the Middle-aged and Elderly Women’s Health Questionnaire to simultaneously evaluate physical health, mental health, health literacy, and family support. Spearman correlation and mediation analysis were used to examine the interrelationships among health literacy and family support with respect to physical and mental health outcomes.</p> Results <p>Health literacy showed a small but statistically significant mediating effect on the association between physical health and mental health (β = 0.008, 95% confidence interval (CI) [0.002, 0.014]), accounting for 2.02% of the total effect. In addition, family support significantly moderated this association (β = 0.013, <i>P</i> = 0.002), such that better physical health was more strongly associated with better mental health at higher levels of family support.</p> Conclusion <p>This study reveals the mediating role of health literacy and the moderating effect of family support in the relationship between physical and mental health in middle-aged and elderly women. The multifactor dynamic interaction mechanism needs to be further explored to guide the formulation of mental health promotion policies.</p>