Cross-border e-commerce, as an innovative format and model of international trade, plays a crucial role in accelerating the transformation and upgrading of industrial structures, and shaping a modern economic framework. Using panel data from 260 prefecture-level cities in China from 2003 to 2019, this study investigates the impact of the cross-border e-commerce comprehensive pilot area (CBECCPA) policy on the upgrading of service industry structure and its mechanisms using the staggered difference-in-differences (DID) method. The results show that the CBECCPA policy can significantly promote the upgrading of service industry structure. The mechanism analysis reveals that the CBECCPA policy can promote the upgrading of service industry structure by clustering service industry enterprises, bolstering urban innovation, and increasing the scale of trade. Heterogeneity analysis indicates that the impact of the CBECCPA policy on the information transmission, software, and information technology service industry is more pronounced and the policy effect is stronger for those with a lower level of service industry structure and for pilot areas with higher levels of development, developmental foundation, developmental scale, and developmental innovation. Furthermore, the policy effect varies significantly across cities. This study provides empirical evidence and policy insights into the role of the CBECCPA in the upgrading of service industry structure.