N-arachidonoylethanolamine (AEA) plays a crucial neuroprotective role in certain neurodegenerative diseases. Our recent studies suggested that AEA analog N-stearoyl-l-tyrosine (NsTyr) could protect neurons from apoptosis and improve hippocampus-dependent learning and memory deficits. The present study was designed to determine the neuroprotective effect of NsTyr on developmental sevoflurane neurotoxicity using primary hippocampal neuronal cultures and rat pups. We found that NsTyr could decrease cell viability and reduce apoptosis in sevoflurane treated neuronal cultures. In addition, NsTyr attenuated sevoflurane-induced apoptosis by modulating Caspase-3 and Bcl-2 in vivo. Moreover, sevoflurane exposure led to an inhibition of phospho-ERK1/2, which was rescued by NsTyr. Administration of U0126 (an inhibitor of MEK) abolished the neuroprotective effect of NsTyr on sevoflurane neurotoxicity both in vitro and in vivo. Finally, administration of NsTyr improved the learning and memory disorders induced by postnatal sevoflurane exposure without alteration in locomotor activity. These results indicated that AEA analog NsTyr protects developing brain against developmental sevoflurane neurotoxicity possibly through MEK/ERK1/2 MAPK signaling pathway.