Achyranthes bidentata Blume is a commonly prescribed Chinese medicinal herb with a variety of pharmaceutical properties. From its aqueous extract we have separated important constituents, referred to as A. bidentata polypeptides (ABPP). In this study, the neuroprotective effect of ABPP against N-methyl-d-aspartate (NMDA)-induced cell apoptosis was investigated in cultured rat hippocampal neurons. The results of MTT assay, Hoechst/PI double staining and DNA ladder detection indicated that ABPP significantly attenuated, in a concentration-dependent manner, apoptotic cell damage induced by exposure of cultured hippocampal neurons to NMDA (100 μM) for 30 min. The intracellular calcium measurement with fluo-3/AM revealed that ABPP antagonized the excess intracellular calcium triggered by NMDA. Furthermore, in addition to inhibiting the action of NR2B-containing NMDA receptors, ABPP can enhance the function of NR2A-containing NMDA receptors. Our data might suggest that ABPP may also prove to be a potential neuroprotective therapy owing to its differential modulation of NR2A- and NR2B-containing NMDA receptors.