Background: Children are at increased risk for respiratory tract infections (RTIs) due to their developing pulmonary functions and immune systems, highlighting the necessity of accurate and rapid pathogen diagnostic methods. While targeted next-generation sequencing (tNGS) has shown higher sensitivity compared to conventional microbiological tests (CMTs), studies focused on pediatric RTIs are limited. Methods: In this study, 940 pediatric patients with RTIs were included who were hospitalized at Qingdao Huangdao District People's Hospital, China, from April 1, 2023, to December 31, 2023. CMTs were conducted during their hospitalization, and a 107-pathogen tNGS panel was applied in pathogen discovery to evaluate its clinical utility and outcomes by comparing it with CMTs. Additionally, the epidemiology of pediatric respiratory pathogens was analyzed across different seasons, ages, and genders. Results: Our study demonstrated that tNGS exhibited significantly higher sensitivity in pathogen detection compared to CMTs, with a detection rate of 91.38%. tNGS was capable of identifying a broader range of pathogens, including low-abundance and RNA viruses frequently missed by CMTs, and it was able to detect mixed infections, whereas CMTs typically identified only a single pathogen. Treatment adjustments based on tNGS results led to clinical improvements in the majority of patients, with 35.32% experiencing escalated treatment plans and 29.04% experiencing de-escalated treatment plans. Additionally, the analysis revealed significant variations in pathogen prevalence across different age groups and seasons, highlighting the need for tailored diagnostic, treatment, and prevention strategies. Conclusions: The findings highlight the potential of tNGS to improve clinical outcomes in pediatric RTIs by providing more accurate and comprehensive pathogen detection. Future research should aim to standardize tNGS methodologies and expand the range of targeted pathogens to further improve diagnostic accuracy.