Insampaedok-san is a traditional medicine used for the treatment of colds. We investigated several compounds in Insampeadok-san, and tested their neuroprotective and anti-oxidative activities after fermentation with Lactobacillus. The amounts of four marker compounds (ferulic acid, hesperidin, 6-gingerol and glycyrrhizin) and unidentified compounds in Insampaedok-san (IS) and fermented Insampaedok-san (FIS) were measured and compared by an established HPLC-DAD method. Neuroprotective activity of IS and FIS extracts was evaluated and compared after glutamate-induced neurotoxicity in HT22 cells. Anti-oxidative activity of IS and FIS was also compared in DPPH free radical, hydroxyl radical and hydrogen peroxide scavenging activity assays. Contents of two compounds, ferulic acid and glycyrrhizin were decreased while 6-gingerol was increased by fermentation. FIS showed more potent neuroprotective activity than IS. DPPH, hydroxyl radical and hydrogen peroxide scavenging was slightly increased by FIS when compared to IS. In conclusion, fermentation with Lactobacillus can vary the amounts of the marker compounds in IS and improve neuroprotective and anti-oxidative activities of IS.