Mycoplasma pneumoniae pneumonia (MPP) is a common type of pneumonia among school-aged children and adolescents. Jinzhen Oral Liquid (JZOL) and Azithromycin (AZ) are commonly used treatments in traditional Chinese medicine (TCM) and Western medicine, respectively. There are several clinical and basic research reports on their solo effect against MPP, enabling their combined treatment to become possible. However, the mechanisms and specific pharmacodynamics of their combined therapy remain unclear. In this study, we conducted a mechanistic analysis of the combination of JZOL and AZ based on network target, elucidating their modular network regulatory mechanisms. The modular mechanisms involve four modules, including hormone response, cell differentiation and migration, signal transduction, oxygen and hypoxia response, centered by TNF signaling pathway-mediated regulation. Under the instruction of computational analysis, we conducted a randomized, double-blind, three-armed, parallel-controlled, multicenter clinical study of different doses of JZOL combined with AZ for the treatment of MPP in children. The objective of clinical research is to evaluate the synergistic effect of different doses of JZOL combined with AZ in the treatment of children with MPP, shortening the course of disease and improving prognosis, while observing the safety of clinical application. At the study endpoint, the median time to clinical recovery showed statistically significant differences (The double-dose group lasts for 5 days, the regular-dose group lasts for 6 days, and the placebo group lasts for 8 days), which were also observed between groups for time to complete fever remission, time to relief of cough/phlegm, effective rate of chest X-ray improvement, and rate of healing of TCM symptoms. Different doses of JZOL combined with AZ have shown the effects of shortening the course of the disease, relieving the symptoms, and improving the prognosis. The research program composed of computational prediction and clinical trials can significantly accelerate the research and development process and identify more effective treatment with good safety, which is worthy of clinical promotion. Chinese Clinical Trial Registry ChiCTR1800019007.