Picroside II is an active constituent extracted from the traditional Chinese medicine (TCM) hu-huang-lian. To evaluate the neuroprotective effect of picroside II, PC12 cells were treated with glutamate in vitro and male ICR mice were treated with AlCl(3) in vivo. Pre-treatment of PC12 cells with picroside II could enhance the cell viability and decrease the level of intracellular reactive oxygen species (ROS) induced by glutamate. By DNA fragmentation and flow cytometry assay, picroside II (1.2 mg/ml) significantly prevented glutamate-induced cell apoptosis. In the animal study, amnesia was induced in mice by AlCl(3) (100 mg/kg/d, i.v.). Pricroside II, at the dose of 20 and 40 mg/kg/d (i.g.), markedly ameliorated AlCl(3)-induced learning and memory dysfunctions and attenuated AlCl(3)-induced histological changes. This was associated with the significant increased superoxide dismutase (SOD) activity in the brain of experimental mice. All these results indicated that picroside II possessed the therapeutic potential in protecting against neurological injuries damaged by oxidative stress.