Background Since varicella is already known to be a globally distributed disease, the focus should be more on its transmissibility or disease burden. The incidence of varicella is affected by natural and socio-economic factors. However, it is unclear how these factors synergetically impact the dynamics of varicella transmission and control.Methods We conducted a retrospective analysis of varicella cases in children aged 0-17 years from 2013 to 2022 in Jiading District, Shanghai, China. First, we evaluated demographic characteristics, epidemiological trends of varicella. And then, we explored the impact of two-dose varicella vaccine (VarV) program on varicella incidence using interrupted time-series analyses, and assessed the influence of natural and socio-economic factors using principal component analysis and multivariate regression. Spatial analysis was conducted to compare varicella epidemiology.Results Our analysis includes 6,482 reported varicella cases, with a higher incidence observed among males (58.67%). Regional differences were noted, with the highest incidence in the western region and the lowest in the central region. Before the implementation of the two-dose VarV program, varicella incidence increased by 0.28 cases per 100,000 per month. Following the two-dose VarV program's introduction, the incidence rate decreased by 0.49 cases per 100,000 per month, with an impressive 79.10% reduction in the annual average incidence among children aged 4-6 years. By analyzing the impact of demographic characteristics, healthcare capacity, economic level, air pollutants, and meteorological factors on the incidence of varicella, we found that the child population ratio and VarV program were most strongly associated with varicella incidence.Conclusion The study underscores the importance of sustained monitoring of child population ratio and VarV program to reduce varicella transmission and protect vulnerable groups.