Cisplatin (CIS) is an effective chemotherapeutic agent used in the treatment of several malignancies. The clinical use of CIS is associated with adverse effects, including acute kidney injury (AKI). Oxidative stress and inflammation are key events in the development of CIS-induced AKI. This study investigated the protective effect of taxifolin (TAX), a bioactive flavonoid with promising health-promoting properties, on CIS-induced nephrotoxicity in mice. TAX was orally given to mice for 10 days and a single dose of CIS was injected at day 7. Serum blood urea nitrogen (BUN) and creatinine were elevated, and multiple histopathological alterations were observed in the kidney of CIS-administered mice. CIS increased renal malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β, and decreased cellular antioxidants in mice. TAX remarkably prevented kidney injury, ameliorated serum BUN and creatinine, and renal MDA, NO, NF-κB p65, and pro-inflammatory cytokines, and boosted antioxidant defenses in CIS-administered mice. TAX downregulated Bax and caspase-3, and upregulated Bcl-2. These effects were associated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase (HO)-1 activity in CIS-administered mice. In conclusion, TAX prevented CIS-induced AKI by mitigating tissue injury, oxidative stress, inflammation, and cell death. The protective efficacy of TAX was associated with the upregulation of Nrf2/HO-1 signaling.