Allylguaiacol is a phytochemical occurring in various plants such as cloves, cinnamon, basil, and nutmeg. Pharmacological effects of allylguaiacol include antimicrobial, anti-inflammatory, anticancer, antioxidant, and neuroprotective activity. Although allylguaiacol is considered to have neuroprotective effects, there is no report on its regulatory mechanisms at the molecular level. In the present study, we investigated the mechanisms of allylguaiacol as an antioxidant and neuroprotective agent using hydrogen peroxide (H2O2)-treated HT22 hippocampal cells. Allylguaiacol increased the scavenging activities of free radicals 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH), and enhanced the expression of antioxidant enzymes manganese superoxide dismutase (MnSOD) and catalase. In addition, allylguaiacol inhibited H2O2-induced damage of HT22 with increasing production of brain-derived neurotrophic factor (BDNF), phosphorylation of phosphoinositide 3-kinase (PI3K), and cyclic AMP response element-binding protein (CREB). Furthermore, antibody microarray data revealed that phospho-regulation of nuclear factor kappa B (NF-κB) p65 and death domain-associated protein (DAXX) is involved in protection against neuronal cell damage. In a mouse model of short-term memory impairment, allylguaiacol (2.5 or 5 mg/kg) significantly ameliorated scopolamine-mediated cognitive impairment in a passive avoidance task. In addition, allylguaiacol significantly increased the expression of TrkA and B in the hippocampus from scopolamine-treated mice. Taken together, our findings suggest that allylguaiacol exerts a neuroprotective effect through the antioxidant activation and protein regulation of NF-κB p65 and DAXX-related signaling. The ameliorating effect of allylguaiacol may be useful for treatment of memory impairment in Alzheimer's and its related diseases.