University plays a crucial role in China’s national innovation system. Accelerating university innovation and enhancing its quality are vital means to establish a new pattern of innovation-driven development. This study takes the National Independent Innovation Demonstration Zone (NIIDZ), a regional independent innovation policy, as a quasi-natural experiment, and uses a panel dataset of 1247 Chinese universities from 2006-2019, empirically investigates the impact and mechanism of regional innovation policy on university innovation based on the staggered DID model. The study finds that the establishment of NIIDZs sustainably promotes the quantity and quality of university innovation R&D output, and effectively enhances universities’ innovation spillover effects. Mechanism analysis indicates that the policy primarily enhances university innovation R&D output by utilizing synergies among industry-university research collaboration, R&D talent clustering, and basic research transformation. Heterogeneity analysis reveals that the establishment of NIIDZs can enhance the quantity and quality of innovation R&D output more effectively in strategic emerging industries, in collaborative R&D between university and non-university innovation entities, and in leading universities. This study provides practical basis for accelerating China’s independent innovation and improving the construction of strategic scientific and technological strength of universities in the new development period.