<p>Sepsis-associated encephalopathy (SAE) is a serious neurological complication of systemic infection, marked by cognitive deficits, neuroinflammation, and increased mortality. Microglial activation and proinflammatory signaling pathways, particularly involving IL-17a and NF-κB, are key contributors to SAE pathogenesis. Cordycepin (3′-deoxyadenosine), a bioactive nucleoside analog from <i>Cordyceps militaris</i>, exhibits potent anti-inflammatory and immunomodulatory effects, yet its role in SAE remains largely unexplored. In this study, a cecal ligation and puncture (CLP) mouse model was used to evaluate the neuroprotective effects of cordycepin. Behavioral tests showed that cordycepin significantly improved cognitive performance in septic mice. 16S rRNA sequencing showed that cordycepin restored gut microbial diversity disrupted by sepsis. Immunofluorescence analysis demonstrated preserved hippocampal neuronal integrity and attenuated neuroinflammation following treatment. Mechanistically, cordycepin suppressed peripheral Th17 cell expansion, reduced IL-17a levels in both circulation and brain tissue, and downregulated IL-17RA/NF-κB signaling in hippocampal microglia. Furthermore, it promoted polarization of microglia toward the anti-inflammatory M2 phenotype. Collectively, these findings suggest that cordycepin alleviates SAE by modulating the gut–immune–brain axis, suppressing IL-17a/IL-17RA/NF-κB signaling, and enhancing microglial M2 polarization, thereby offering a promising therapeutic strategy for sepsis-related cognitive impairment.</p> Graphical Abstract <p></p>