Acute renal failure is a serious complication of treatment with the anticancer drug cisplatin. Cisplatin exerts a cytotoxic effect on renal cells by inducing apoptosis through activating the tumor suppressor p53, nuclear factor‑κB (NF‑κB) and mitogen‑activated protein kinase (MAPK)/p38 pathways. Effects of protein extracts of the brown seaweed Porphyra yezoensis (P. yezoensis) on cytotoxicity, inflammation and cell proliferation have been reported; however, the effects of P. yezoensis protein (PYP) extract on cisplatin‑induced renal injury have remained elusive. The present study investigated the effects of PYP on cisplatin‑induced nephrotoxicity in the HK2 human proximal tubular epithelial cell line. PYP treatment reduced cisplatin‑induced apoptosis and death of HK2 cells by restoring the B‑cell lymphoma‑2 (Bcl‑2)‑associated X protein (Bax)/Bcl‑2 imbalance, cytochrome c release and caspase‑3 activation. In addition, PYP activated the redox‑sensitive transcription factor NF‑κB via stimulating the nuclear translocation of p65 in HK2 cells. PYP also restored renal antioxidant levels and increased the total and nuclear accumulation of NF erythroid 2‑related factor 2 in HK2 cells. PYP markedly attenuated cisplatin‑induced p38, MAPK and c‑Jun N‑terminal kinase phosphorylation. Furthermore, treatment with PYP ameliorated cisplatin‑induced renal cell damage by upregulating antioxidant defense mechanisms and downregulating the MAPK and NF‑κB signaling pathways. In addition, mice were divided into three treatment groups (control, cisplatin and PYP + cisplatin) and the effects of PYP were evaluated in a mouse model of cisplatin‑induced acute kidney injury. The concentrations of blood urea nitrogen and serum creatinine in the PYP + cisplatin group were lower than those in the cisplatin group. The mRNA expression levels of inflammatory factors interleukin‑6 (IL‑6), IL‑1β, tumor necrosis factor‑α and monocyte chemoattractant protein‑1 in the kidney tissues of the PYP + cisplatin group were also lower than those in the cisplatin group. These results suggest that PYP treatment had a preventive effect on nephrotoxicity, specifically by downregulating the MAPK and NF‑κB signaling pathways and the mRNA levels of inflammatory genes.