In the context of uncertain internal and external development environment, improving regional economic resilience through optimizing and adjusting regional spatial structure is of great significance to achieve high-quality economic development. The effect of polycentric spatial structure on regional economic resilience and its mechanism are analyzed and tested empirically. The results show that polycentric spatial structure has significant role in promoting regional economic resilience. Polycentric spatial structure promotes regional economic resilience by promoting technological innovation level and upgrading industrial structure. In addition, it is found that in the eastern region and the regions with higher level of economic development, the polycentric spatial structure has a more significant role in enhancing regional economic resilience, and the polycentric spatial structure has a greater role in enhancing regional economic resilience when economic resilience is at a low level. The findings have important implications for policy making to improve regional economic resilience from the spatial perspective.