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Isoflurane-induced neuroinflammation triggers cognitive impairment in aged mice, but its underlying mechanism remains unclear. This study investigated the molecular mechanism by which isoflurane promotes glycolytic reprogramming to cause cognitive dysfunction in aged mice and identified potential therapeutic targets. 18-month-old mice were placed in an anaesthetic induction chamber containing 2% isoflurane (ISO) for 2 h to induce anaesthesia; this procedure was repeated daily for 5 days to establish a model of age-related cognitive impairment in mice. Behavioural studies in mice were conducted using the Y-Maze, contextual fear conditioning test (CFCT), Novel Object Recognition (NOR) test, and water maze test. Immunofluorescence analysis was employed to detect changes in the expression of microglia-related proteins PGK1, Hip, iNOS, Arg1, and P65. RT-PCR was employed to detect changes in mRNA expression levels of GLUT2, PKM2, HK2, and LDHA, which are associated with cellular metabolic reprogramming. ELISA was used to measure alterations in TNF-β, IL-4, IL-10, IL-6, IL-1β, and TNF-α cytokines. ISO enhanced glycolytic flux via PGK1, thereby driving microglia polarization toward the pro-inflammatory M1 phenotype and triggering neuroinflammation, ultimately leading to cognitive impairment in mice. Supplementing the glycolytic intermediate FBP reversed the anti-inflammatory effects induced by PGK1 knockdown, confirmed that PGK1 exerted its effects through the "PGK1-glycolysis axis." Mechanistically, PGK1 knockdown effectively suppressed M1 polarization of microglia while promoting their transition to the anti-inflammatory M2 phenotype. This significantly mitigated ISO-induced neuroinflammation and neuronal injury, ultimately improving cognitive function in mice. These findings reveal that PGK1 serves as a key molecular link between ISO anaesthesia and neuroinflammatory cognitive impairment. Targeting and inhibiting PGK1 exerts neuroprotective effects by reprogramming microglial glucose metabolism and phenotype, providing novel theoretical insights and potential therapeutic strategies for preventing ISO-induced neurological complications.