In the present study, the protective effects of quercetin on peripheral neurotoxicity caused by vincristine, which is used effectively in the treatment of various types of cancers, were investigated by using different techniques. In the study, for 12 days, male Sprague Dawley rats were given 25 and 50 mg/kg doses of quercetin orally and were administered a 0.1 mg/kg dose of vincristine (a total cumulative dose of 1.2 mg/kg) intraperitoneally 30 minutes later. The protein levels of nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase-1 (NQO1), glial fibrillary acidic protein (GFAP), and nuclear factor kappa B (NF-κB) were measured with ELISA; the immunopositivity of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and caspase 3 were determined with immunohistochemistry; the mRNA transcript levels of double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1), activating transcription factor-6 (ATF-6), glucose-regulated protein 78 (GRP78), Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), caspase 3, protein kinase B1/2 (Akt-1/2), and forkhead box transcription factor, class O1 (FOXO1) were determined with RT-PCR. The reduction of Nrf2 levels and HO-1 and NQO1 activities in the sciatic nerve tissue, the increase in the levels of 8-OHdG, and the increase in the levels of GFAP and NF-κB caused by vincristine was observed to cause oxidative stress, oxidative DNA damage, neuronal cell damage, and inflammation, respectively. Additionally, vincristine was determined to cause ER stress and apoptosis by increasing PERK, IRE1, ATF-6, and GRP78 and caspase 3 and Bax expressions and by decreasing Bcl-2 expressions. Vincristine causing Akt inhibition also shows that it prevents neuronal survival. However, quercetin was determined to relieve oxidative stress, oxidative DNA damage, neuronal cell damage, inflammation, ER stress, and apoptosis caused by vincristine and enable Akt activation. These results show that in rats, quercetin may have a protective effect against peripheral neurotoxicity caused by vincristine.Copyright © 2020. Published by Elsevier B.V.