Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), delayed neurocognitive recovery (dNCR) and postoperative neurocognitive disorder (PNCD), affect up to 10% of surgical patients older than 60 years, and currently there are no effective therapies to prevent PND. The gut microbiota is linked to PND through the gut-brain axis, promoting neuroinflammation via activation and proliferation of microglia and astrocytes in the central nervous system (CNS). In this study, we show that perioperative use of ceftriaxone, a long-acting β-lactam antibiotic, can prevent the development of PND in elderly surgical patients. This effect is associated with reduced serum complement C3 levels and increased levels of platelet factor 4 (PF4). Using an aged mouse model of PND, we found that C3/C3aR axis mediated the interaction of astroglia and microglia during the early stages of neuroinflammation. Genetic ablation or pharmacological blockade of C3/C3aR signaling pathway suppressed neuroinflammation and attenuated cognitive declines in PND. The C3/C3aR axis is essential for surgery-induced platelet count and circulating PF4 declines, and mice supplemented with recombinant PF4 exhibited reduced neuroinflammation and improved cognitive function. Together, our findings revealed the new roles of the C3/C3aR signaling pathway in platelet dysfunction and neuroinflammation in age-related PND, and these results highlight new potential therapeutic strategies for PND.