In the context of globalization and urbanization, mobility has expanded the geographical scope of infectious diseases transmission, and the epidemic outbreak has posed big challenges to human health and economic and social steadiness. From a local scale, the natural and social diversity in each region makes it show differentiated characteristics of vulnerability and resilience when facing the epidemic. Therefore, this article focused on the types of infectious diseases which can be transferred by infected person, constructed a vulnerability evaluation index system based on the three dimensions, including exposure, sensitivity and adaptability, used entropy method to identify the spatial differentiated characteristics of vulnerability to infectious disease outbreaks in American counties, utilized various methods containing comprehensively clusters analysis, literature analysis and others to discuss the division of vulnerability types in America counties, and clarified the impact mechanism that affects the vulnerability of infectious disease outbreaks through analyzing the literature. The results are as follows: ①Overall, the vulnerability of infectious disease infection in American counties is mostly at a low or lower level, with relatively significant spatial differentiation characteristics.②Summarize the mechanism of infectious disease outbreaks: The outbreak of infectious disease is driven by natural and anthropogenic disturbance factors, including genetic mutation, biological disasters, land use changes, globalization and the like. Exposure involves social connections at domestic and international scales. Sensitivity involves four aspects, individual risks, urban environment, economic security, and social proliferation. Adaptability involves three aspects, government emergency response, medical systems, and social security. ③Based on the score of the influencing factors of vulnerability of infectious disease outbreaks, American counties are divided into 10 regional types to analyze the driving mechanism of vulnerability.