Alzheimer's disease accounts for the majority of dementia and shows hallmarks such as sequential cognitive dysfunction and abnormal behavior. Dendropanax morbifera (DM) has traditionally been used to treat a variety of diseases in East Asia. The aim of this study was to assess the therapeutic effects of DM on brain neuron damage and on cognitive deficit in neuronal cell induced by Aβ1-42 in mice. Treatment with DM reduced the levels of intracellular reactive oxygen species and protected against the death of neuronal cells induced by Aβ1-42 peptide. In addition, it was also found that pretreatment with DM decreased cognitive damage induced by Aβ peptide via enhancing the cholinergic system and antioxidant defense system in mice. Furthermore, the study verified that the change in the expression of both cyclic-adenosine monophosphate response element binding protein and of brain-derived neurotrophic factor in the hippocampus in Aβ peptide-treated mice was significantly ameliorated after treatment with DM. Accordingly, these results suggest that pretreatment with DM defends against oxidative stress and cognitive impairment caused by Aβ peptide.