<p>China’s high-speed rail (HSR) network has rapidly expanded into peripheral and less-developed counties, raising important questions about its impact on innovation in these areas. While HSR holds the potential to foster innovation spillovers, it may also reinforce core-periphery disparities through a siphoning effect. This study investigates the causal impact of HSR on innovation in peripheral counties within China’s Yangtze River Delta region. Using panel data from 191 counties, we employ a difference-in-differences framework, complemented by propensity score matching and Bacon decomposition, to address potential selection bias and heterogeneous treatment timing. We also adopt an instrumental variable approach to establish a causal relationship between HSR and county-level innovation. The empirical results indicate that HSR significantly enhances county-level innovation by promoting knowledge collaboration and financial market vitality. However, these positive effects tend to be temporary and conditional on local contexts. Notably, the benefits are more pronounced in peripheral counties with stronger economic and innovation foundations, pointing to considerable heterogeneity in HSR’s impact. The findings are robust across alternative model specifications and variable definitions, highlighting the dual impact of HSR and underscoring the need for targeted innovation policies to sustain its benefits in peripheral regions.</p>