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The global economic situation is in a downturn, and the upgrading of manufacturing structure is a necessary transformation path for the manufacturing industry to achieve high-speed and stable development. The article analyzes the theoretical mechanism of the digital economy affecting the upgrading of manufacturing structure through the endogenous economic growth model, constructs a three-stage mediation effect model, and empirically researches the path of the digital economy affecting the upgrading of manufacturing structure in the Pearl River Delta. The study finds that the digital economy has a significant positive promoting effect on the upgrading of manufacturing structure. In terms of the influencing mechanism, the enhancement of the level of independent innovation and the advancement of the human capital structure are the important paths of the digital economy in promoting the upgrading of manufacturing structure. Among them, the mediating effect is 17.5% for the level of independent innovation and 17.4% for the level of the advancement of the human capital structure. The results of the study also found that the upgrading of manufacturing structure cannot be separated from government support, and the influence of government support on t the upgrading of manufacturing structure reaches 44.9%, and government deployment and control is conducive to accelerating the process of advanced manufacturing structure.