Transportation infrastructure construction plays an important role in the development of economy and industry, and the construction of high-speed railway (HSR) is highly valued as a gas pedal to promote economic growth and accelerate the industrial upgrading of cities. Based on the panel data from 285 Chinese cities from 2004 to 2019, the impact and spatial effects of HSR construction on urban industrial upgrading was examined using a spatial difference-in-differences model. The study revealed several key findings. The operation of HSR has a significant effect on the industrial upgrading of station cities, and the effect strength increases with the increase of the city's centrality in the HSR network. The opening of HSR in the station cities has a spatial spillover effect on the industrial upgrading of the surrounding cities, and it has a spatial attenuation boundary, which ranges from 150 km to 1250 km depending on the centrality of the station city. From the perspective of action path, the construction of HSR facilitates the transfer of industries between station cities and non-station cities within the region, as well as between the central cities of HSR network in the region between regions, and thus promotes the industrial upgrading of cities. We propose to deepen regional industrial division, strengthen intra-regional industrial synergy and articulation, create a pan-HSR economic belt, and provide unimpeded and orderly channels for industrial transfer between regions, so as to fully unleash the industrial upgrading driving effect of HSR and promote regional industrial synergy and upgrading.