Manufacturing upgrading not only aligns with the contemporary implications of the domestic-international "dual circulation" development paradigm, but also serves as a critical driving force in the process of modernization. Using urban panel data from 2005 to 2021, the opening of the "Yixin'ou" China-Europe Railway Express was treated as a quasi-natural experiment. A double machine learning model was constructed to examine the impact of international transportation corridors on manufacturing industry upgrading and its underlying mechanisms. Research has found that the opening of the "Yixin'ou" China-Europe Railway Express can significantly promote the upgrading of the manufacturing industry. Technological innovation and trade growth are important paths for the upgrading of the manufacturing industry affected by the opening of the "Yixin'ou" China-Europe Railway Express. The opening of the "Yixin'ou" China-Europe Railway Express has shown significant heterogeneity in its impact on the upgrading of the manufacturing industry. Specifically, cities located on the northeast side of the "Qing-Da Line", cities with a high degree of manufacturing industry agglomeration, and cities with strong local fiscal autonomy have a more significant upgrading effect on their manufacturing industry. It expands the economic effect dimensions of the China-Europe Railway Express, providing policy implications for the high-quality development of the "Yixin'ou" China-Europe Railway Express.