Acute hypobaric hypoxia (HH) gives rise to persistent cognitive impairment, influencing memory function specifically. Echinacoside (ECH), one of the phenylethanoids isolated from the stems of Cistanche salsa, has been reported to prevent ischemia induced by neuronal injury traditionally. This study then tried to investigate whether ECH could alleviate HH‐induced memory deficit. Ten C57 mice were used as control, and 50 were exposed to HH equivalent to 6,100 m for 7 days in a decompression chamber and were given ECH daily (50, 75, or 100 mg/kg) through gavage during the period of exposure. Cognitive performance was evaluated by the Morris water maze test. ECH, especially at 100 mg/kg, significantly reduced HH‐induced memory decline. Furthermore, ECH increased the expression of nuclear factor E2 p45‐related factor 2, heme oxygenase‐1, NAD(P)H:quinone oxidoreductase 1, and γ‐glutamyl cysteine synthetase in mRNA and protein levels, suggesting that the Keap1–Nrf2–ARE signaling pathway might be involved in neuronal adaptation. The results indicate that ECH could prevent HH‐induced memory impairment, which is associated with antioxidant effect of ECH in the hippocampus.