In order to promote economic growth and coordinated regional development, the Chinese government has built and operated more than 25,000 km of high-speed rail. Local governments have made a huge investment in high-speed rail construction, aiming to promot economic agglomeration around stations by compressing spatial distance, and produce a spillover effect on the local economy. However, it still needs to test whether high-speed rail construction can change the development fate of these cities. In this paper, the economic impact of high-speed rail opening on these cities was examined by considering cities along China's “four vertical and four horizontal” high-speed rail lines as observation objects and using “night lighting data,” key economic indicators, and the difference-in-difference model with matching method. The following findings were obtained in our study. First, high-speed rail opening failed to promote the economic growth of cities along high-speed rails in the short term, but accelerated the economic diffusion of cities along high-speed rails over time. Second, high-speed rail opening had a significant impact on the industrial structure of cities along high-speed rails, increased the proportion of the tertiary industry and reduced the proportion of the secondary industry. Third, high-speed rail construction exerted a greater influence on the economic development level of big cities and had no significant impact on the economic development level of small and medium-sized cities along the high-speed rails. In the robustness test, consistent results were obtained by replacing the economic growth measurement methods, changing the time breakpoint and conducting a counterfactual test.