We examined whether a crude methanol extract of Angelica gigas (AgMx) improved the spatial cognitive impairment induced by repeated immobilization (IMO) stress in rats. The effects of AgMx on hippocampal expression of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) were also investigated. For 21 days, male rats received daily doses of AgMx (20, 50, or 100 mg/kg, i.p.) 30 min prior to daily exposure to IMO stress (6 h/day). The daily administration of AgMx improved memory impairment, as measured by the passive avoidance test, and reduced the escape latency for finding the platform in the Morris water maze test. Additionally, as assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis, the administration of AgMx significantly alleviated memory-associated decreases in the expression levels of BDNF and CREB proteins and mRNAs in the hippocampus. Thus, these findings suggest that AgMx may be useful as a therapeutic agent in various neurodegenerative diseases for improving cognitive function. It effects likely involve the regulation of BDNF and CREB expressions.