Cisplatin-induced kidney injury (CIKI) is a major adverse effect of this widely used chemotherapy agent. Targeting key events involved in CIKI, such as inflammation, apoptosis, mitochondrial dysfunction and oxidative stress, holds potential for mitigating CIKI and improving patient outcomes. Herein, we report a novel N-containing chalcone derivative as a cysteine-targeting covalent binder of Keap1, which effectively mitigate cisplatin (CDDP)-induced mitochondrial dysfunction (CIMD) and CIKI through activating Keap1-Nrf2-ARE signaling. Initially, a chalcone derivative (A6) was identified as a strong Nrf2 agonist through high-throughput luminescence screening of in-house compounds. After two rounds of structural optimization, we developed a novel N-containing chalcone derivative (C5), which exhibits enhanced Nrf2 agonist activity, favorable drug-like properties, and improved renal-targeting ability. Cellular and animal studies showed that C5 significantly ameliorated CIMD and CIKI in CDDP-induced nephrocytes and CIKI mice via activating the Keap1-Nrf2-ARE signaling pathway in both settings. Mechanistically, C5 covalently modified Keap1 on two critical functional cysteines in Keap1 (Cys288 in the IVR domain and Cys319 in the Kelch domain), synergistically amplifying Nrf2 activation. As an extremely potent Nrf2 agonist, C5 mitigated CIKI by orchestrating antioxidant defenses, boosting mitochondrial energetics, promoting mitochondrial biogenesis, restoring mitochondrial dynamics, and inhibiting subsequent apoptotic cascade activation. Furthermore, Nrf2 knockdown markedly attenuated the nephroprotective effects of C5 in CIKI mice, confirming the critical role of Keap1-Nrf2 signaling in its nephroprotective mechanism. Collectively, a novel N-containing chalcone derivative was developed as an efficacious and renal-targeting covalent binder of Keap1, offering a promising therapeutic candidate for combating CIKI.