Six new sesquiterpenoids (1–6), named calamusins L–Q, together with fourteen known ones were isolated from the ethanol extract of the rhizomes of Acorus calamus. The new compounds and their absolute configurations were determined based on extensive spectroscopic analyses and computational methods. All of the new compounds were evaluated for their neuroprotective effect against serum withdrawal, rotenone, and OGD-induced PC12 cell injury, and it was revealed that compounds 1 and 6 increased the cell survival rate of the OGD-treated PC12 cells moderately at 10 μM.