Kidney injury is one of the common side effects in cancer patients receiving chemotherapy. Enhancement of renal antioxidant and anti-inflammation function are important strategies to combat chemotherapy-induced kidney injury. In this study, we successfully isolated a novel water-soluble polysaccharide from Poria cocos sclerotia (Poria cocos polysaccharides (PCP), molecular weight: 55.245 kDa), which features an α-1,4-D-Glcp backbone with branches linked at the O-6 positions. In vitro, PCP significantly relieved oxidative damage and apoptosis caused by the chemotherapeutic agent cisplatin in renal tubular epithelial cells (RTECs). In vivo, pretreatment with PCP attenuated cisplatin-induced kidney injury by mitigating oxidative stress, apoptosis, and inflammation. Furthermore, post-treatment with PCP facilitated the recovery of renal function following kidney injury. In chronic kidney injury model, PCP exhibited a persistent nephroprotective effect in inhibiting the progression of chronic kidney disease and fibrosis. Mechanistically, PCP protected RTECs from cisplatin by activating the nuclear transcription factor E2-related factor 2 (Nrf2) signaling pathway. Importantly, PKCζ was identified as the upstream kinase responsible for initiating the phosphorylation activation of Nrf2. Taken together, PCP confers protection against cisplatin-induced kidney injury by activating the PKCζ-Nrf2 signaling pathway, suggesting that PCP may be a promising clinical candidate for the treatment of chemotherapy-induced kidney injury.