Health-related quality of life (HRQoL) is an interesting topic in health care sciences and psychology. Deeper insight into the internal mechanism of this effect through large samples is crucial to further understanding HRQoL and making targeted suggestions to improve HRQoL. The present study aims to investigate the mediating role of interpersonal trust between age and HRQoL from a developmental lens. The purpose of this study was to profile the Pediatric Quality of Life Inventory 4.0 generic scale in China and test the relationship between age and health-related quality of life, as well as the mediating role of interpersonal trust and the moderating role of gender. A sample of 6248 children completed measures of demography, health-related quality of life, and interpersonal trust. Regression analyses were performed to test the mediating role of interpersonal trust and the moderating role of gender. Age was associated with lower health-related quality of life and lower interpersonal trust. Similarly, gender differences were also noted, with boys reporting higher health-related quality of life and lower interpersonal trust than girls. Additionally, the health-related quality of life of girls declined more than that of boys with increasing age. Regression analyses revealed that age could predict decreased health-related quality of life via lower levels of interpersonal trust. What is more, the mediation effect was moderated by gender, with the observed mediation effect being stronger among boys than girls. The current study replicates age and gender differences in health-related quality of life and interpersonal trust. Moreover, this study explained how and when age affected the health-related quality of life of children, and provided a deeper understanding of the relation between age and health-related quality of life.