To observe the preventive effect of modified Huangqi Guizhi Wuwu Decoction on oxaliplatin induced peripheral neurotoxicity (oipn), and explore the possible mechanism of modified Huangqi Guizhi Wuwu Decoction in preventing OIPN. Methods Forty healthy WISTA female rats were randomly divided into blank group, model group, glutathione (GSH) group and traditional Chinese medicine group, with 10 rats in each group. The model group, traditional Chinese medicine group and GSH group were repeatedly injected with oxaliplatin solution (2.5mg/kg, diluted with 5% glucose solution) intraperitoneally on days 1, 2, 8, 9, 15, 16, 22 and 23 for modeling rats of OIPN. The blank group was injected with the same volume of 5% glucose solution intraperitoneally. The GSH group was injected with glutathione 1.5g/m2/d tail vein on the day of chemotherapy and two days before and after chemotherapy. The traditional Chinese medicine group was gavaged with modified Huangqi Guizhi Wuwu Decoction (10ml/kg, once a day). The blank group, the model group and GSH group were gavaged with 0.9% normal saline (10ml/kg, once a day).Von Frey test was used to detect the threshold of mechanical foot retraction reflex on days 0, 7, 14, 21 and 28. The rats were killed on day 28. The spinal cord and L4-5 dorsal root ganglion were isolated. The activity of spinal cord peroxidase, ROS fluorescence of dorsal root ganglion cells and the expression level of p53 Bax pathway related mitochondrial apoptotic protein were detected.Results Compared with the blank group, the mechanical foot contraction threshold of the model group decreased continuously (P＜0.01), the activities of SOD and GSH-Px decreased significantly (P＜0.01), the content of MDA increased significantly (P＜0.01), and the fluorescence intensity of ROS in DRG cells increased significantly (P＜0.01). Compared with the model group, the traditional Chinese medicine group and GSH group were better than the model group in mechanical foot contraction threshold, peroxidase activity and ROS fluorescence intensity (P＜0.05), and the traditional Chinese medicine group was better than GSH group in peroxidase activity (P＜0.05). Compared with the model group, the traditional Chinese medicine group could significantly reduce the expression of p53, Bax and caspase-3 protein and increase the expression of Bcl-2 protein in DRG cells (P＜0.01). Conclusion Modified Huangqi Guizhi Wuwu decoction can prevent oipn through antioxidant stress and inhibiting mitochondrial damage of DRG cells induced by p53-Bax pathway