With the acceleration of globalization and the increasing frequency of population movement, the cross-border transmission of major infectious diseases poses a continuous threat to China’s public health security. This paper analyzes the risks and challenges of cross-border transmission of major infectious diseases faced by China, explores prevention and control strategies and countermeasures, and proposes establishment of an overseas-border-domestic whole-chain prevention and control system for cross-border importation of major infectious diseases based on the synergy of medicine, prevention and management. The aim is to provide theoretical support and practical pathways for enhancing China’s capacity to prevent and control the cross-border transmission of major infectious diseases.