The incidence of cognitive impairment is rising globally, but there is no effective therapy. Recent studies showed that fucoidan (Fuc), a sulfated polysaccharide enriched in brown algae, is widely used due to its anti-inflammatory, antioxidant, and prebiotic effects. However, the effects and mechanisms of Fuc on lipopolysaccharide (LPS)-induced neuronal cell damage and cognitive impairment in mice need to be explored further. In the present study, we found that Fuc treatment protected HT22 cells from LPS-induced damage by inhibiting the activation of NLRP3 inflammasomes. Fuc exerted neuroprotective effects in mice with LPS-induced cognitive impairment by ameliorating neuroinflammation, promoting neurogenesis, and reducing blood-brain barrier and intestinal barrier permeability. Mechanistically, Fuc supplement significantly restructured the gut microbiota composition, which may be related to glucose and fructose metabolism. In conclusion, Fuc ameliorated LPS-induced neuronal cell damage and cognitive impairment in mice, suggesting that Fuc may be a medicinal and food homologous functional agent to improve cognitive function.