Amyloid-β peptide (Aβ) plays a causal role in the development and progression of Alzheimer's disease (AD). Oxidative stress and activation of mitogen-activated protein kinase (MAPK) are involved in Aβ-induced neurotoxicity. Morroniside, one active monomer of dry ripe sarcocarp of Cornus officinalis, has shown antioxidant properties in several cell lines. The present study investigated the protective actions of morroniside against the cytotoxicity produced by exposure to H2O2 or Aβ1–42 in rat pheochromocytoma (PC12) cells. Exposure of PC12 cells to 150μM H2O2 or 20μM Aβ1–42 down-regulated anti-apoptotic protein expression (Bcl-2), up-regulated pro-apoptotic protein expression (Bax, cytochrome C, and cleaved caspase-3), increased JNK and p38 MAPK phosphorylation and finally caused significant cell death. This effect was reversed by pretreatment with morroniside in a dose-dependent manner. Among the selective inhibitors of MAPKs, the JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580) showed steady preventive effect against H2O2 or Aβ1–42-induced apoptosis. The results suggest that different from the selective inhibitors of MAPKs, morroniside can inhibit H2O2 or Aβ1–42-induced apoptotic pathway activation through suppressing its upstream signaling components of JNK and p38 MAPK phosphorylation simultaneously.