The sudden outburst of COVID-19 in 2020 has a serious impact on China’s macro-economy，which also reflects the Index for Mass Entrepreneurship and Innovation （IMEI）. During the period of the epidemic，the scores of the Index for Mass Entrepreneurship and Innovation in most cities have declined to a certain extent. However，the decline of the IMEI differ by cities：the cities with low initial scores declined more relative to those cities with high initial scores；about the three first-level indicators，i.e.，environmental support，resource capacity and value of efficiency，the cities with low initial environmental support scores or value of efficiency scores decline more in the IMEI scores，while the change of resource capacity scores of different cities did not show the similar pattern. In addition，from the perspective of urban stratification based on the status of entrepreneurship and innovation，the impact of the epidemic has enlarged the variation within each stratification. The response pattern of negative shock not only highlights the importance of the evolution law of the urban system in promoting the work of entrepreneurship and innovation，but also provides an enlightenment for the further design of promoting the entrepreneurship and innovation.