Abstract Objectives This study aims to explore key factors and identify root factors influencing the Public Health Emergency Response Mechanism (PHERM) to ensure timely and effective responses to emerging infectious disease crises and enhance the efficiency of emergency operations. Methods We employed a mixed-method approach using DEMATEL-ISM-MICMAC to analyse the interrelationships among factors affecting PHERM. The DEMATEL method established the hierarchical structure of the factors, ISM determined the relational paths, and MICMAC further characterized the attributes of the factors. Results The analysis revealed that PHERM's influencing factors are organized into four levels, with the conscientiousness of emergency leadership action (X15) identified as the most profound and influential factor, exhibiting a strong causality with a high driving force. The decision-making and command feedback capability (X8) emerged as a significant outcome factor in the transition layer, highly influenced by other factors and with the highest node degree. Conclusions The proactive emergency response awareness and actions of leaders is crucial for the mechanism's smooth and efficient operation. It is essential to prioritise ideological education and simulation training to instill such awareness. Moreover, proactive preparation for factors associated with decision-making and command capabilities is necessary to mitigate potential hesitation and panic during actual epidemic prevention, thereby enhancing the operational effectiveness of PHERM.