Background <p>Although cisplatin is an effective chemotherapy, a major downside is its toxicity, including cerebellar neurotoxicity, which is mediated by the induction of inflammation and oxidative stress. On the other hand, daflon, a micronized purified flavonoid fraction, suppresses inflammation and oxidative stress. However, the effect of daflon on cisplatin-induced cerebellar neurotoxicity has not been documented.</p> Aim <p>The present study evaluated the effect of daflon in cisplatin-induced cerebellar toxicity. In addition, the role of TLR4/NF-kB signaling was explored.</p> Materials and methods <p>Twenty male Wistar rats were acclimatized for 2 weeks and then randomized into 4 equal groups: control, daflon-treated, cisplatin-treated, and cisplatin+daflon-treated.</p> Results <p>Daflon significantly improved cisplatin-induced distortions in cerebellar histology, evidenced by increased thickness in the molecular and intergranular layers, increased Purkinje cells, and reduced pyknotic neurons. Also, daflon attenuated cisplatin-induced rise in malondialdehyde and cisplatin-driven decline in glutathione, superoxide dismutase, and catalase activities. Furthermore, daflon ameliorated cisplatin-induced rise in myeloperoxidase activity and tumour-necrosis factor α, interleukin-1β 1β, and interleukin-6 levels. Additionally, daflon suppressed cisplatin-induced upregulation of toll-like receptor-4, nuclear factor-kappa B, cyclo-oxygenase-2, prostaglandin E2, and caspase-3 activity in the cerebellar tissue.</p> Conclusion <p>In conclusion, daflon confers neuroprotection against cisplatin-induced cerebellar neurotoxicity through the suppression of TLR4/NF-kB-mediated oxidative-inflammatory and apoptotic injury.</p>