Lactobacillus-derived extracellular vesicles (Lac-EVs) reduce inflammation caused by lipopolysaccharide (LPS) in microglial cells, promoting the differentiation of M2 macrophages and exhibiting anti-inflammatory effects. Perioperative neurocognitive dysfunction (PND) is a common complication in elderly patients, with inflammation playing a significant role. The gut microbiota influences the intestinal barrier and can trigger systemic inflammation, which may affect the central nervous system (CNS). Lactobacillus, a probiotic, can modulate immune function and cognitive behavior. Extracellular vesicles (EVs) are novel therapeutic carriers that can target the CNS. This study investigated the effect of Lac-EVs on neuroinflammation and microglial polarization. In vitro experiments showed that Lac-EVs reduced the expression of proinflammatory cytokines (IL-1β and IL-6) and increased IL-10 production after LPS stimulation. The mRNA expression of M1-labeled protein (iNOS) decreased, while that of M2-labeled protein (Arg1) increased. Flow cytometry revealed a significant change in the ratio of M1/M2 microglia. Lac-EVs promoted the differentiation of M2 microglia by inducing the expression of specific markers related to M2 macrophages. These findings suggest that Lac-EVs can alleviate inflammation-driven PNDs by modulating microglial polarization. The study also demonstrated that Lac-EVs can cross the blood-brain barrier and regulate microglial differentiation. The results indicate that Lac-EVs have potential as an effective anti-inflammatory strategy for treating neuroinflammation and PNDs. The research highlights the importance of understanding the microbiota-gut-brain axis and the role of probiotic-derived EVs in modulating CNS function. The study provides insights into the mechanisms by which probiotics can influence neuroinflammation and offers a promising approach for the treatment of neurodegenerative and inflammatory diseases.Lactobacillus-derived extracellular vesicles (Lac-EVs) reduce inflammation caused by lipopolysaccharide (LPS) in microglial cells, promoting the differentiation of M2 macrophages and exhibiting anti-inflammatory effects. Perioperative neurocognitive dysfunction (PND) is a common complication in elderly patients, with inflammation playing a significant role. The gut microbiota influences the intestinal barrier and can trigger systemic inflammation, which may affect the central nervous system (CNS). Lactobacillus, a probiotic, can modulate immune function and cognitive behavior. Extracellular vesicles (EVs) are novel therapeutic carriers that can target the CNS. This study investigated the effect of Lac-EVs on neuroinflammation and microglial polarization. In vitro experiments showed that Lac-EVs reduced the expression of proinflammatory cytokines (IL-1β and IL-6) and increased IL-10 production after LPS stimulation. The mRNA expression of M1-labeled protein (iNOS) decreased, while that of M2-labeled protein (Arg1) increased. Flow cytometry revealed a significant change in the ratio of M1/M2 microglia. Lac-EVs promoted the differentiation of M2 microglia by inducing the expression of specific markers related to M2 macrophages. These findings suggest that Lac-EVs can alleviate inflammation-driven PNDs by modulating microglial polarization. The study also demonstrated that Lac-EVs can cross the blood-brain barrier and regulate microglial differentiation. The results indicate that Lac-EVs have potential as an effective anti-inflammatory strategy for treating neuroinflammation and PNDs. The research highlights the importance of understanding the microbiota-gut-brain axis and the role of probiotic-derived EVs in modulating CNS function. The study provides insights into the mechanisms by which probiotics can influence neuroinflammation and offers a promising approach for the treatment of neurodegenerative and inflammatory diseases.