Neonatal　hypoxic-ischemic　brain　damage　(HIBD)　is　considered　as　a　major　cause　of　long-term　cognitive　impairments　in　newborns.　It　has　been　demonstrated　that　gut　microbiota　is　closely　associated　with　the　prognosis　of　various　neurological　disorders.　However,　the　role　of　microbiota-gut-brain　axis　on　cognitive　function　following　neonatal　HIBD　remains　elusive.　In　this　experiment,　the　correlation　analysis　supported　the　involvement　of　gut　microbial　changes　following　hypoxic-ischemic　(HI)　insult　in　the　development　of　long-term　cognitive　impairments.　Subsequent　experiment　revealed　the　involvement　of　the　intestinal　dysfunction　in　the　hippocampal　neuroinflammation　and　synaptic　injury.　In　causal　relationship　validation　experiments,　fecal　microbiota　transplantation　(FMT)　from　cognitively　normal　rats　could　restore　gut　microbial　composition,　improve　intestinal　dysfunction,　reduce　the　serum　levels　of　lipopolysaccharides　(LPS)　and　inflammatory　mediators,　and　alleviate　neuroinflammation,　synaptic　damage　and　cognitive　impairments　in　neonatal　HIBD　recipient　rats.　Conversely,　the　FMT　from　neonatal　HIBD　rats　could　induce　above　adverse　pathological　changes　in　the　normal　recipient　rats.　Moreover,　oral　administration　of　anti-inflammatory　agent　dexamethasone　(DEX)　exhibited　the　potential　to　alleviate　these　detrimental　effects　in　neonatal　HIBD　rats,　with　the　efficacy　being　partly　reliant　on　gut　microbiota.　Further　experiment　on　the　potential　molecular　mechanisms　using　RNA　sequencing　indicated　a　significant　increase　in　the　toll-like　receptor　4　(TLR4)　gene　in　the　intestinal　tissues　of　neonatal　HIBD　rats.　Additionally,　the　interventions　such　as　TLR4　inhibitor　TLR4-IN-C34　administration,　FMT,　and　oral　DEX　were　demonstrated　to　modulate　intestinal　function　by　inhibiting　the　LPS/TLR4　signaling　pathway,　thereby　exerting　neuroprotective　effects.　Collectively,　these　findings　underscore　the　contribution　of　gut　microbial　dysbiosis　post　HI　insult　in　activating　the　LPS/TLR4　signaling　pathway,　triggering　intestinal　inflammation　and　dysfunction,　exacerbating　systemic　inflammation,　and　consequently　worsening　synaptic　and　cognitive　impairments　in　neonatal　HIBD　rats.　Hence,　rectifying　gut　microbial　dysbiosis　or　regulating　intestinal　function　may　represent　a　promising　strategy　for　alleviating　long-term　cognitive　impairments　in　neonates　affected　by　HIBD.