N-methyl-D-aspartate (NMDA) receptor has important role in synapse function and neurotransmission by the high permeability of Ca²⁺. In Alzheimer's disease (AD), NMDA mediated neurotransmission is impaired by decreasing NMDA receptor subunits and increasing glutamate, which is an NMDA receptor ligand. Therefore, the NMDA antagonist (memantine) is used as a therapeutic drug of AD. Huperzia serrata is a traditional Chinese herbal medicine, and the constitute huperzine A has been reported to inhibit NMDA receptor. In this study, we clarified the effect of Huperzia serrata and the constitute huperzine A on MK-801-induced cognitive dysfunction. Memantine, Huperzia serrata and huperzine A were administered orally once a day and Y-maze test was performed at day 7 to investigate cognitive function. After Y-maze test, mice brains were collected and evaluated the expression levels of glutamate receptors and Ca²⁺ signalling associated protein. Memantine (5 mg/kg, p.o.), Huperzia serrata (1000 mg/kg, p.o.) and huperzine A (0.7 mg/kg, p.o.) were improved collect alternation behaviour in Y-maze test. Treatment of memantine, Huperzia serrata and huperzine A also improved the total arm entries increased by MK-801. The expression level of NMDA receptor subunit NR2A was increased by Huperzia serrata and huperzine A treatment. In addition, the decreased expression level of PKCα and phosphorylation of Erk1/2 by MK-801 were improved. These results suggest that Huperzia serrata and the constitute huperzine A improve cognitive dysfunction through NMDA receptor function and glutaminergic signaling pathway.