Currently, the excessive activation of N-methyl-D-aspartate receptors (NMDARs) is considered to be a crucial mechanism of brain injury. Lycium barbarum A (LyA) is a dimer of phenol amides isolated from the fruit of Lycium barbarum. Our previous studies have shown that LyA has potential antioxidant activity. This study aimed to explore the neuroprotective effect of LyA and its potential mechanism. Firstly, the molecular docking was used to preliminarily explore the potential function of LyA to block NMDAR. Then, the ability of LyA was further verified by NMDA-induced human neuroblastoma SH-SY5Y cells in vivo. Treatment with LyA significantly attenuated NMDA-induced neuronal insults by increasing cell viability, reducing lactate dehydrogenase (LDH) release, and increasing cell survival. Meanwhile, LyA significantly reversed the increase in intracellular calcium and in ROS production induced by NMDA. Finally, the western blot indicated that LyA could suppress the Ca influx and increase the p-NR2B, p-CaMKII, p-JNK, and p-p38 level induced by NMDA. These above findings provide evidence that LyA protect against brain injury, and restraining NMDARs and suppressing mitochondrial oxidative stress and inhibiting cell apoptosis may be involved in the protective mechanism.