Building a comprehensive national science center is an important strategic measure to adapt to the global innovation development pattern, enhance China’s innovation capacity and achieve high-quality development. It is of great theoretical value and practical significance to study the influence mechanism of building comprehensive national science centers on innovation ability and scientifically evaluate the policy effect of building comprehensive national science centers. In this paper, the influence mechanism of comprehensive national science centers on regional innovation capability is explored from the aspects of large science device cluster, innovation resource element clustering, knowledge spillover and technology diffusion, collaborative innovation system construction and innovation ecosystem construction. At the same time, Hefei Comprehensive National Science Center in Anhui Province was selected as a quasi-natural experiment. Based on the panel data of 22 provinces and cities from 2009 to 2021, the synthetic control method was used to empirically test the impact of comprehensive national science Center on innovation capability. The empirical results showed that: Comprehensive national science centers have a certain enhancement effect on innovation ability, and the robustness test also supports this conclusion. According to the above conclusions, this paper proposes to increase the investment and construction of national science centers and promote the deep integration of innovation chain and industrial chain.