Objective To investigate the effect of piceatannol (PIC) on rat brain damage caused by acute carbon monoxide (CO) poisoning through the mitogen-activated protein kinase / extracellular siganl-regulated kinase(MAPK/ ERK) pathway. Methods SPF male SD rats was randomly assigned to four groups( 25 rats each group). Three groups were infused with CO gas for 1 hour to establish an acute CO poisoning model. The negative control (NC) group did not receive any CO. Following removal from the CO, the percent of carboxygenhemoglobin(HbCO%) of the rats in all four groups was determined immediately. Subsequently, the PIC group received 2 mL 200 mg / kg PIC by intragastric administration, the PIC + ERK group was similarly treated with both 2 mL 200 mg / kg PIC and 0. 2 mg / kg ERK inhibitor P-4313, and the CO and NC groups were treated with an equal volume of normal saline. A water maze experiment was performed after 1, 7, 14, 21 and 28 d. After completing this experiment, the brain tissues of all the animals were obtained for hematoxylin-eosin (HE) staining observation, Terminal deoxynucleotidyl transferase-mediated dUTP Nick-End labeling(TUNEL) staining to detect cell apoptosis, ultrastructure observation of neurons in brain tissue, detection of mitochondrial membrane potential, detection of the oxidative stress damage index of brain tissue cells, and Western blot detection of the nuclear factor E2 related factor 2(Nrf-2) and B-cell lymphoma-2(Bcl-2) proteins. Results In comparison with the NC group, rats in the CO and PIC + ERK groups displayed poorer learning and memory performance in the water maze experiment, the brain tissue cell morphology was changed, the ultrastructure of nerve cells was disrupted, the number of apoptotic cells was greater (P< 0.001), the mean fluorescence intensity(MFI) value was significantly decreased ( P< 0. 001) and the reactive oxygen species(ROS) content was elevated (P<0. 001). In contrast with the CO group, rats in the PIC group were normal in the behavioral experiments and the brain tissue cell morphology did not change; furthermore, fewer apoptotic cells were found (P<0. 001), the ultrastructure of nerve cells was intact, the MFI value and ROS content were lower (P<0. 001), and the Nrf-2 and Bcl-2 protein expression were slightly increased. Conclusions PIC may increase Nrf-2 and Bcl-2 expression through the MAPK/ ERK signaling pathway to protect against brain damage caused by acute carbon monoxide poisoning.