Influenza is an acute respiratory infection that spreads rapidly and widely in densely populated areas with low vaccination coverage. The trends and drivers of the spatial and temporal dynamics of influenza incidence among residents of mainland China have not been systematically studied. This study comprehensively analyses the dynamics and spatial correlation of influenza using long-term scale data and spatial panel data. It then identifies the interactive process of socio-economic and natural elements on the incidence of influenza. The highest prevalence of influenza was found in the 0-4 years age group in mainland China (mean prevalence, 67.56/100,000). In addition, influenza in mainland China shows seasonality, with fall and winter being the periods of high incidence. Between 2014 and 2017, influenza incidence was clustered in Hubei and Anhui provinces, and the spatial clustering was statistically significant (Z value > 1.96, P < 0.05). Moreover, the directionality of influenza onset continued to increase each year. Specifically, the clustering of influenza onset was stronger in the northwest-southeast direction than in the southwest-northeast direction between 2014 and 2018. The significant role of socioeconomic factors as a primary influence on influenza incidence, while their interaction with natural factors, such as air quality (NOx and PM2.5) and climatic conditions can exacerbate regional outbreaks. This study provides a novel perspective for better prevention and control of influenza disease among mainland Chinese residents.