Bortezomib (BTZ), a proteasome inhibitor, causes dose-limiting peripheral neuropathy in humans. Berberine (BBR), which has various biological and pharmacological properties, is known to have neuroprotective properties. The possible protective effects of BBR on peripheral neuropathy caused by BTZ were investigated in this study. For this purpose, BTZ was intraperitoneally given to Sprague dawley rats on the 1 st, 3rd, 5th, and 7th days with a cumulative dose of 0.8 mg/kg. Moreover, animals were orally administered 50 or 100 mg/kg BBR daily from day 1 to day 10. As a result of the analyzes performed on the sciatic nerve and spinal cord, it was observed that MDA levels and NRF-2, HO-1, NQO1, GCLC and GCLM mRNA transcript levels increased due to oxidative stress caused by BTZ, and the levels of these markers decreased after BBR administration. Also, it was determined that SOD, CAT, GPx and GSH levels increased after BBR treatment. It was observed that BTZ caused inflammation by triggering NF-κB, TNF-α, IL-1β and IL-6 cytokines, on the other hand, with BBR treatment, these cytokines were suppressed and inflammation was alleviated. In addition, it was determined that the expressions of RAGE, STAT3, NLRP3 and TLR4, which have important roles in inflammation, increased with BTZ administration, but BBR suppressed the expressions of these genes. It was determined that the expressions of SIRT1, which plays an important role in neuropathic pain, and CREB-LI neurons, which has an active role in neurite outgrowth and survival, decreased with BTZ administration. It was observed that GFAP levels increased with BTZ administration and decreased with BBR administration. Given all the findings, it was concluded that BBR exhibits protective qualities in the sciatic nerve and spinal cord induced by BTZ.