Cisplatin is a widely used chemotherapeutic agent. Nevertheless, a significant fraction of cisplatin-treated patients develops nephrotoxicity which limits cisplatin therapeutic implementation. The current work was devoted to investigate the potential nephroprotective impact of theaflavin against the cisplatin-induced nephrotoxicity using male Wistar rats as a mammalian model. The results indicated that theaflavin significantly improved the renal histopathological picture and glomerular filtration rate, along with reduced renal injury marker KIM-1, urinary albumin/creatinine ratio, serum creatinine, and urea. Mechanistically, theaflavin upregulated protein level of SIRT1 and downregulated the acetylated forms of the inflammatory transcription factor (TF) NF-kB, the antioxidant TF FOXO3a, and the pro-apoptotic TF p53 in the cisplatin-treated rats. Additionally, it upregulated the antioxidant TF Nrf2. In the same context, it suppressed the inflammatory responses, oxidative stress, and apoptosis. NF-kB nuclear translocation and levels of its responsive gene products IL-6 and TNF-α were suppressed. Lipids and DNA oxidation were reduced, and level of the antioxidant GSH and activity of the antioxidant enzymes SOD, GPx, and CAT were increased. The apoptotic markers caspase-3, BAX, and Bcl2 were modulated. Collectively, these findings highlight the nephroprotective competency of theaflavin against cisplatin-induced nephrotoxicity and underscore modulations of SIRT1, p53, FOXO3a, Nrf2, and NF-kB as potential targets.