Edible bird’s nest (EBN), abundant in sialic acid (SA) has been recognized as a natural substance beneficial to brain development and cognitive ability. In order to investigate active component of EBN, sialylated glycopeptides (SCP) were extracted from EBN by 60% ethanol after trypsin hydrolysis and its effects on central nervous system was evaluated in lipopolysaccharide (LPS)-induced neuroinflammation mice. EBN, SCP, and SA pretreatment and intervention reduced interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels in hippocampus and cortex, meanwhile inhibited the activation of microglia, astrogliosis and neuron apoptosis, which were consistent with the learning and memory improvement and anti-depression effects in behavioral tests. The counts of leukocytes, neutrophils and monocytes, as well as IL-1β, TNF-α, and IL-6 levels in peripheral circulation were significantly reduced by SCP. Results of plasma metabolomics suggested SCP up-regulated energy metabolism, promoted the recovery of primary and secondary bile acid metabolism and indole metabolism, where microbiota may involve. 16S rDNA sequencing of colonic contents showed EBN, SCP and SA repaired dysbacteriosis in LPS-treated mice by significantly up-regulating the anti-inflammatory Muribaculaceae and inhibiting pro-inflammatory related Desulfovibrio and Candidatus_Saccharimonas. In addition, both EBN and SCP could significantly enrich Aerococcus, while SA could specifically enrich Prevotellaceae_UCG_001. The gut-brain axis was preliminarily established, and SCP may have the potential to be a functional factor for neuroprotection applied in EBN industry.