In this study, a mixed-methods research approach was employed, integrating social network analysis, descriptive analysis, and inferential statistical analysis to examine the health topic subject directories and the interconnections among health topics within the subject directory system of the MedlinePlus portal. One hundred and fifty-nine health topics related to children’s health as well as 1457 qualified keywords were collected and analyzed. As a result, 184 new connections (140 bidirectional and 44 unidirectional) were proposed to be added to the original subject directory on MedlinePlus. Five new core topics were identified as influential topics in the subject network. This new optimized structural network was proved to be significantly improved from the original one and the importance of the newly identified core topics were verified. The evaluations also included participants containing both medical professionals (2) and medical students (31). The user evaluation results confirmed that the recommendations suggested by this study are solid and effective. The findings of this research would improve the information searching effectiveness for the portal users and offer insights to public health portal creators.