Background: Chemotherapy-induced peripheral neuropathy (CIPN) is common in pateints undergoing chemotherapy. Hexuetongbi (HXTB), a TCM, could treat CIPN. Objective: This study investigates HXTB in treating CIPN and the underlying mechanism in an oxaliplatin-induced rat model (model). Methods: The rat model was developed by intraperitoneal injection of oxaliplatin for four weeks. The HXTB was investigated on the behavior of rats. Network analysis, TCMSP, and GeneCards were used to identify CIPN targets and HXTB therapeutic entities. HXTB and CIPN molecular pathways were analyzed using GO enrichment and KEGG. H&E staining assessed dorsal root ganglion neuron morphology. qRT-PCR and Western Blot evaluated mRNA and protein levels. Results: The model group had significantly higher frequency of CPWR and lower MWT. HXTB reduced CPWR and increased MWT. H&E staining demonstrated abnormal neuron morphology, confirming model development. HXTB neurons remained normal. Skin, liver, kidney, and heart function were preserved. Network analysis identified 19 active HXTB constituents and 35 CIPN targets. Among the 35 targets, the PI3K/Akt signaling pathway was the main pathway identified. PI3K, Akt1, Akt2, and Bcl-2 mRNA and protein levels were up-regulated. Conclusion: HXTB can ameliorate CIPN by regulating the PI3K/Akt and Bcl-2 pathways to inhibit apoptosis of damaged dorsal ganglion neurons.