Cisplatin is one of the most potent chemotherapy drugs widely used for cancer treatment. However, its use is limited by side effects in normal tissues, particularly the kidneys. Recent studies, using both in vitro and in vivo experimental models, have suggested a critical role for p53 in cisplatin nephrotoxicity. The signaling pathways upstream and downstream of p53 are being investigated and related to renal cell injury and death. Along with the mechanistic studies, renoprotective approaches targeting p53 have been suggested. Further research may integrate p53 signaling with other nephrotoxic signaling pathways, providing a comprehensive understanding of cisplatin nephrotoxicity and leading to the development of effective renoprotective strategies during cancer therapy.