Background. Renal cell carcinoma (RCC) is the most prevalent form of kidney cancer and is the primary malignancy affecting the genitourinary system. It represents the majority of kidney cancer cases and is distinguished by its aggressive nature and high mortality rate. The current study investigates the chemoprotective effect of myrrhone against Diethylnitrosamine (DEN) and ferric nitrile (Fe-NTA) induced RCC in rats and elucidates the underlying mechanism. Methods. Following a single dose of intraperitoneal DEN (200 mg/kg) and a twice-weekly administration of Fe-NTA, rats were administered either an oral dose of myrrhone (5, 10, or 15 mg/kg). The body weights and food intake of the rats were monitored at regular intervals, and the levels of renal cancer markers, antioxidants, inflammatory markers, and other parameters were assessed. Additionally, histopathological studies were conducted on the renal tissues, and the mRNA expression of Bax, Bcl-2, HO-1, SOD2, mtDNA, ATP8, PGC-1 alpha, TRL4, and NF-kappa B was analyzed. Results. The dosage-dependent administration of myrrhone demonstrated a remarkable suppression of tumor incidence and an improvement in body weight and food intake. Myrrhone markedly decreased the level of ODC, Thymidine [3H] incorporation, and renal parameters such as creatinine, uric acid, BUN, Kim-1, Cysc-C, and LDH. Additionally, myrrhone significantly altered the levels of MDA, GSH, GPx, CAT, and SOD, as well as inflammatory cytokines such as TNF-alpha, INF-gamma, IL-1 beta, IL-6, and IL-10, and inflammatory parameters such as COX-2, PGE2, TGF-beta 1, NF-kappa B, and iNOS. Furthermore, myrrhone significantly decreased the histopathological score and improved the condition of histopathology. Finally, myrrhone significantly altered the mRNA expression of Bax, Bcl-2, HO-1, SOD2, mtDNA, ATP8, PGC-1 alpha, TRL4, and NF-kappa B. Conclusion. The result clearly showed the chemoprotective effect of myrrhone against diethylnitrosamine and ferric nitrile induced Renal Cancer via alteration of HO-1/Nrf2 and TRL4/NF-kappa B Signaling pathway.