ABSTRACT High‐speed rail (HSR), as a new type of transportation infrastructure in China, has a significant impact on promoting county‐level economic development and advancing common prosperity through its efficient and convenient transportation mode. This study uses data from 1854 county‐level administrative regions in China from 2004 to 2018 and employs the difference‐in‐differences (DID) method to empirically analyze the impact of HSR opening on entrepreneurial activity in counties and its mechanism. The research findings indicate that the opening of HSR significantly increases the number of new enterprises in counties, and this conclusion remains valid after addressing endogeneity issues and robustness tests. However, the average effect masks significant heterogeneity in terms of industry types and geographical locations. The impact of HSR on county‐level entrepreneurial vitality is more pronounced in eastern regions, areas with low topographic relief, and county‐level cities with a higher level of economic development. Meanwhile, the effect of HSR operation on entrepreneurship is moderated by county size and government scale. Specifically, the larger the county size and the smaller the government intervention, the more significant the role of HSR operation in promoting county‐level entrepreneurial activity. Furthermore, when adjacent regions are connected to HSR, some spillover effects occur. Enhancing technological innovation levels, promoting economic agglomeration, and expanding market consumption potential are important channels through which HSR enhances entrepreneurial activity in counties.