Objective To investigate the effects of huperzine A on ameliorating acute hypobaric hypoxic-induced spatial learning and memory deficits, and on relieving the apoptosis of hippocampal neurons in rats. Methods Forty-eight SD rats were randomly divided into four groups (12 each): the champaign (plain) group (control group), champaign+huperzine A group, high altitude group (simulated 6000m plateau) and high altitude+huperzine A group. One day before the decompression simulation experiment, rats in huperzine A-treated groups were given intragastrically with huperzine A suspension (10mg/ml) in a dose of 0.1mg/kg. The spatial learning and memory performance of rats in each group were tested by Morris Water Maze. The apoptosis of hippocampal neurons was determined by TUNEL. The expression of pro-apoptotic proteins (Bax) and anti-apoptotic protein (Bcl2) of hippocampus tissues were evaluated by Western blotting. Results Compared with those in high altitude group, significantly shortened escape latency (P<0.05), more platform crossing within 60s (P<0.05), longer retention time in target (P<0.05), lower rate of hippocampal neurons apoptosis (P<0.05), down-regulated expression of Bax (P<0.05) and up-regulated expression of Bcl2(P<0.05) in the hippocampus tissues were found in the high altitude+huperzine A group. However, no significant difference in the above mentioned findings was found between high altitude+huperzine A group and champaign control group. Conclusion Huperzine A treatment may have a protective effect against acute hypobaric hypoxic-induced apoptosis of hippocampal neurons in rats, and it ameliorates spatial learning and memory deficits in rats.