<p>Chlorpyrifos (CPF), a widely used pesticide, is associated with significant renal toxicity, raising concerns about its impact on kidney health. Selenium nanoparticles (Se NPs) have emerged as a potential therapeutic agent due to their beneficial properties. This study evaluated the effects of Se NPs against CPF-induced nephrotoxicity, focusing on oxidative stress, inflammation, and the SIRT1/Nrf2/HO-1 signaling pathway. Rats were administered CPF, with or without Se NPs, for 28 days. Renal function was assessed through biochemical markers, histopathological examination, and molecular analyses. CPF exposure significantly elevated serum creatinine, blood urea nitrogen, and Kim-1 levels, accompanied by histopathological damage in renal tissues. Se NPs treatment effectively restored renal function and attenuated structural abnormalities. CPF-induced oxidative stress was evident through increased lipid peroxidation and suppressed antioxidant enzymes and reduced glutathione (GSH), which were counteracted by Se NPs. Furthermore, CPF upregulated pro-inflammatory and apoptosis mediators (NF-κB, TNF-α, IL-6, iNOS, Bax, and caspase-3), while downregulating the anti-apoptotic Bcl-2. Se NPs mitigated these effects by suppressing inflammatory and apoptotic pathways, effects associated with decreased Keap1 and enhanced SIRT1, Nrf2, and HO-1. In conclusion, Se NPs confer protection against CPF-induced kidney injury by alleviating oxidative stress, inflammation, and apoptosis, and by modulating the SIRT1/Nrf2/HO-1 signaling. These findings underscore the potential of Se NPs as a therapeutic intervention for CPF-associated nephrotoxicity.</p> Graphical Abstract <p></p>