Abstract: This study investigated the effects of Lacticaseibacillus rhamnosus B6 metabolic products of fermented skim milk (LB6S) on synaptic vesicle proteins (Syp) in human neuroblastoma SH-SY5Y cells and their protective mechanism against lipopolysaccharide (LPS)-induced neuroinflammatory injury. The viability of SH-SY5Y cells was assessed via the CCK-8 assay to determine the optimal concentration of LB6S. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were employed to analyze Syp expression. An LPS-induced neuroinflammatory model was established to evaluate LB6S-mediated regulation of pro-inflammatory cytokines, apoptotic factors and signaling pathways through RT-qPCR and WB. The results indicated that LB6S exhibited no cytotoxicity at concentrations up to 500 μg/mL (P>0.05). At 500 μg/mL, LB6S significantly upregulated transcriptional expression of the synapse-related genes Sirt1, Syp, Vamp2, and Vglut1 (P<0.05) and increased Syp levels (P<0.05). In LPS-damaged cells, 500 μg/mL LB6S downregulated the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 (P<0.05). Mechanistically, LB6S inhibited neuroinflammation by modulating mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways, reducing pro-apoptotic Bax and increasing anti-apoptotic Bcl-2 expression (P<0.05). In conclusion, LB6S regulates synaptic proteins, promotes Syp expression, and ameliorates neuroinflammatory injury by modulating apoptotic and inflammatory mediators through MAPK/NF-κB signaling.