Objective To explore the effectiveness of different intervention strategies in response to outbreaks of emerging highly pathogenic respiratory infectious diseases (RIDs) in mega-city in China, and provide decision-ma-king basis for effective response to emerging RIDs. Methods A susceptible-exposed-infectious-recovered (SEIR) transmission dynamics model was constructed, referencing to and combining the pathogenicity and infectivity para-meters of previous emerging RIDs. The outbreak of emerging highly pathogenic RIDs with low, moderate, and high infectivity in a mega-city with a population of 10 million in China was simulated, the development of the epidemic within 100 days after implementing different combinations of non-pharmaceutical interventions (NPIs) in response to the outbreak was compared. Results When highly pathogenic RIDs outbreak occurred, and if its infectivity was low (R₀ was about 1.5), it was unnecessary to adopt strict NPIs to control epidemic. If its infectivity was moderate (R₀ was about 6), different intensities of NPIs were needed based on its existing infection scale. When the initial number of infected cases was 50, moderate-intensity NPIs could keep the infection and death at a low level within 100 days, and the required bed number in hospital for cases could be kept below the national average reserve level. But when the scale of infection exceeded 100 cases, high-intensity NPIs were needed to control the development of the epidemic. In the case of extremely strong infectivity (R₀ was about 10), regardless of the scale of infection, only immediate high-intensity NPIs could control the epidemic, infection and death scale. Conclusion In case of outbreaks of highly pathogenic RIDs, adopting appropriate NPIs as early as possible based on their epidemiological characteristics and infection scale is necessary to minimize the harm to the population.