Abstract: Innovation infrastructure, as a core component of the national innovation system, is a key driver in enhancing the resilience of the innovation chains. Based on the fit theory, panel data from 30 provinces in mainland China from 2011 to 2023 were collected. The entropy-weighted TOPSIS method and the entropy method were employed to measure innovation chain resilience and innovative infrastructure development levels. The impact of innovative infrastructure on innovation chain resilience and its underlying mechanisms were examined, followed by robustness, endogeneity, and heterogeneity tests. The findings reveal that innovative infrastructure is demonstrated to exert a significantly positive impact on innovation chain resilience, with knowledge flow, industrial structure and innovation environment being identified as mediating variables. The enhancing effect of innovative infrastructure on innovation chain resilience is observed to strengthen considerably as knowledge flow levels are elevated and the innovation environment is improved, while its marginal effect is found to decrease progressively with the optimization and rationalization of industrial structure. Moreover, distinct regional heterogeneity is confirmed in infrastructure's influence, where the promotional effect is measured to be substantially more pronounced in eastern China compared to central and western regions. Accordingly, three policy measures are recommended: a tiered and well-matched innovative infrastructure system needs to be constructed to achieve coordinated development across basic research, technology transfer and industrial application; innovation infrastructure clusters should be developed to optimize knowledge flow and industrial structure; and the synergy between innovative infrastructure and innovation environment must be enhanced while complementary mechanisms are perfected to safeguard innovation activities.