Based on the panel data of 108 cities in the Yangtze River Economic Belt from 2009 to 2019, this study combines the difference-in-differences (DID) method with the mediation effect model to examine the impact of the opening of high-speed rail (HSR) on regional green innovation performance. It is found that the opening of HSR has significantly improved the regional green innovation performance, and this boosting effect shows an increasing trend over the years. In addition, the impact of the opening of HSR on regional green innovation performance varies significantly depending on geographic location and city size. Further, the measurement of the centrality of the HSR network employing social network analysis (SNA) indicates that the communication ability of node cities’ transportation pulse is increasing, and the connection breadth of the HSR network has a positive impact on the regional green innovation performance. The findings supplement the current economic and environmental effects of HSR and provide a new idea and direction for understanding the relationship between HSR and regional green innovation and optimizing the layout of the HSR networks.