Chlorpyrifos (CPF) is a broad-spectrum insecticide widely employed in agricultural field for pest control. Exposure to CPF is associated with serious effects to the main organs, including kidneys. Significant evidence denotes that oxidative stress (OS) and inflammation are implicated in CPF toxicity. This study aimed to evaluate the potential of farnesol (FAR) to modulate inflammatory mediators and farnesoid-X-receptor (FXR) and Nrf2 in a rat model of CPF nephrotoxicity. CPF and FAR were orally supplemented for 28 days and blood and kidney samples were collected for investigations. CPF administration elevated blood creatinine and urea, kidney MDA and NO, and upregulated NF-κB p65, IL-1β, TNF-α, iNOS, and caspase-3. In addition, CPF upregulated kidney Keap1, and decreased GSH, antioxidant enzymes, and Nrf2, FXR, HO-1 and NQO-1. FAR ameliorated creatinine and urea, prevented histopathological alterations, decreased MDA and NO, and enhanced antioxidants in CPF-administered rats. FAR modulated NF-κB p65, iNOS, TNF-α, IL-1β, caspase-3, Keap1, HO-1, NQO-1, Nrf2 and FXR. In silico investigations revealed the binding affinity of FAR towards Keap1 and FXR, as well as NF-κB, caspase-3, iNOS, and HO-1. In conclusion, FAR prevents CPF-induced kidney injury by attenuating OS, inflammation, and apoptosis, effects associated with modulation of FXR, Nrf2/HO-1 signaling and antioxidants.