Propofol, an intravenous anesthetic agent, exhibits neuroprotective effects against cerebral ischemia–reperfusion injury. Here, we used a model of Hypoxia/Re-Oxygenation (H/R) injury to examine the hippocampal neuroprotective effect of propofol, and explored the role of Nerve Growth Factor (NGF) and NGF receptor TrkA in this action. Rat hippocampal neuron cells were subjected to H/R with different concentrations propofol, the viability and apoptosis of the cells were then determined by MTT assay and annexin V flow cytometry, respectively. Meanwhile, expression of NGF and TrkA were measured by RT-PCR and Western blot. The results showed that H/R significantly reduced viability and increased apoptosis of cultured hippocampal neuron cells, along with the significantly decreased expressions of NGF and TrkA. However, pretreatment of propofol recovered the expressions of NGF and the receptor TrkA, resulting in significantly decreased H/R-induced neurotoxicity. C-Jun N-terminal kinase (JNK) inhibitor suppressed the effect of propofol on the NGF expression, and the TrkA was decreased by PD98059, the Erk1/2 signal blocker. Administration of TrkA inhibitor altered the neuroprotective effect of propofol. These findings suggested the potential of propofol for protecting hippocampal neuron against H/R through at least partly, NGF/TrkA signaling pathway.