The aim of the present study was to investigate the neuroprotective effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, against neuron toxicity induced by glucose deprivation, excitatory amino acids and hydrogen peroxide (H2O2) in cultured rat cerebellar granule cells. Cell membrane damage was measured with a lactate dehydrogenase (LDH) release assay and 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to assess mitochondrial activity, reflecting cell survival. Results showed that honokiol and magnolol alone did not affect mitochondrial function and cell damage, but significantly reversed glucose deprivation-induced mitochondrial dysfunction and cell damage. The glutamate receptor blocker MK-801 and antioxidant vitamin E also provided protection against this damage. Furthermore, honokiol was more potent than magnolol in protecting against glutamate-, N-methyl-d-aspartate (NMDA)- and H2O2-induced mitochondrial dysfunction. These results demonstrated that the neuroprotective effects of honokiol and magnolol may be related to their anti-oxidative actions and antagonism of excitotoxicity induced by excitatory amino acids, suggesting that both compounds may be potential therapeutic agents for neurodegenerative diseases.