The rapid development of high-speed rail has brought about the rapid development of the overall economy and the change of small cities. On the one hand, it is difficult to determine whether the opening of high-speed rail will serve as a “corridor” or an “engine” role for the development of small cities. On the other hand, the growing expansion of big cities is also squeezing the development space of smaller cities. In this context, whether small cities can take the opening of high-speed railway as an opportunity to give play to the advantages of high-speed rail in a larger scope and at a deeper level, and thereby get rid of the development dilemma caused by regional disadvantages, becomes a very realistic problem naturally. In addition, as a major improved public service, high-speed rail will affect people’s regional identity and willingness to settle down, and speed up the frequency and scope of population movement. Therefore, it is more worth studying to pay attention to the population flow in small cities in the era of high-speed rail. Therefore, this paper takes the sample panel data of small cities from 2010 to 2018 as the research object, and adopts the research method of PSM-DID to discuss the impact of high-speed rail opening on the population hollowing-out in small cities and its internal influence mechanism. It is found that the opening of high-speed rail reduces the size of permanent resident population in small cities significantly, so small cities face the risk of population hollowing-out. Through the heterogeneity analysis, this paper finds that for small cities of different sizes, the degree of population loss caused by high-speed rail operation is also different. The results show that the population loss of small cities with an urban population of 0-200 thousand is much lower than that of small cities with an urban population of 200-500 thousand. The mechanism test results show that high-speed rail causes the population hollowing-out in small cities by leading to the outflow of consumer demand, the lag of industrial structure upgrading and the increase of housing prices. Further research finds that the construction of high-speed rail does not lead to a gap in economic growth between small cities with high-speed rail and those without high-speed rail. At the same time, the internal growth gap between small cities with high-speed rail has not been effectively verified. The possible contributions are as follows: First, it broadens the research scope of existing literature, which focuses on the analysis of the impact of high-speed rail opening on central and regional cities, or the impact on the surrounding cities of a high-speed rail line. However, there is a lack of research on the impact of cities of the same scale, especially the quantitative research on the development of small cities by the opening of high-speed rail. Based on the sample panel data of small cities, this paper adopts the PSM-DID method to focus on the study of the impact of high-speed rail opening on population hollowing-out in small cities, which can effectively alleviate the impact of the omission of important variables and systematic bias on the results. Second, it reveals the internal influence mechanisms of population outflow from small cities caused by the opening of high-speed rail. Among them, the outflow of consumption demand in small cities caused by high-speed rail, the lag of industrial structure upgrading, and the increase of housing prices are the important ways to cause population hollowing-out.