Abstract: The aim of the present study was to investigate the protective effects and underlying mechanisms of Garcinia xanthochymus, a perennial medicinal plant native to Yunnan, China, against H₂O₂-induced oxidative damage in rat pheochromacytoma PC12 cells. Preincubation of PC12 cells with fruit EtOAc fraction (fruit-EFr., 12.5-50 μmol·L^-1) of G. xanthochymus for 24 h prior to H₂O₂ exposure markedly improved cell viability and increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase-1HO-1), prevented lactate dehydrogenase release and lipid peroxidation malondialdehyde production, attenuated the decrease of matrix metalloproteinases (MMP), and scavenged reactive oxygen species (ROS). Fruit-EFr. also reduced BAX and cytochrome C expression and improved BCL-2 expression, thereby decreasing the ratio of BAX to BCL-2. Fruit-EFr. activated the nuclear translocation of NRF2 to increase HO-1 and induced the phosphorylation of AKT. Its cytoprotective effect was abolished by LY294002, a specific inhibitor of PI3K. Taken together, the above findings suggested that fruit-EFr.of G. xanthochymus could enhance cellular antioxidant defense capacity, at least in part, through upregulating HO-1 expression and activating the PI3K/AKT pathway and that it could suppress H₂O₂-induced oxidative damage via PI3K/AKT and NRF2/HO-1 signaling pathways.