The spatial arrangement of firms is crucial in determining a region’s economic vigor and potential. Transportation infrastructure, especially high-speed rail (HSR), has become a pivotal element affecting the geographical allocation of economic activities, attracting considerable scholarly interest. This research conducts a thorough investigation of the effects of HSR on enterprise distribution, emphasizing its spatial and temporal variability. The study employs a geographically weighted model (GTWR) to analyze the dynamic link relationship between HSR and enterprise distribution entry. The analysis utilizes a robust data set of newly registered firms across diverse industries at the prefecture-level city scale level, offering a broad overview of market entry trends. The study examines both the direct effects of HSR operation and its indirect impacts on accessibility and connectivity. The research indicates that HSR construction operation positively influences national enterprise distribution, but with spatial and temporal discrepancies. The western region is the most impacted, succeeded by the central and eastern regions, owing to its inadequate transportation infrastructure. Smaller cities are more significantly affected than megacities, as HSR improves their market accessibility. Of China’s five principal metropolitan agglomerations, the Chengdu-Chongqing region is most significantly impacted by HSR, whilst the Yangtze River Delta and Pearl River Delta see lesser effects. The study emphasizes the necessity of accounting for spatiotemporal effects variation when evaluating the effects of transportation infrastructure on economic activities, with considerable significance for policymakers.