Peripheral neurotoxicity is a common adverse reaction in cancer patients undergoing chemotherapy. The neuropathologic changes were partly associated with mitochondrial dysfunction and autophagy. Tanshinone IIA, a compound extracted from the medicinal herb Salvia miltiorrhiza, has been shown to exhibit neuroprotective effects. The present study investigated the effects of tanshinone IIA on chemotherapy-induced neurotoxicity and to study the underlying mechanism. Neuroma cell line N2a and rats were treated with oxaliplatin and/or tanshinone IIA. The effects on neurotoxicity were evaluated using cell viability assay, flow cytometry detection of apoptosis, measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (psi m), autophagy detection, nerve function assessment, and behavior assessment. The results showed that tanshinone IIA prevented oxaliplatin-induced inhibition of cell viability and reduced apoptosis. Tanshinone IIA also prevented excessive oxidative stress, as demonstrated by decreased ROS levels and reduced Wm loss. Lastly, treatment with tanshinone IIA promoted autophagy through the PI3K/Akt/mTOR signaling pathway. The in vivo experiment showed that tanshinone IIA ameliorated oxaliplatin-induced allodynia and sciatic nerve dysfunction. An increase in serum nerve growth factor level was observed. In conclusion, the results of the study suggested a protective role of tanshinone IIA in neurotoxicity induced by oxaliplatin via mitochondrial protection and autophagy promotion.