The most prevalent component of the volatile oil found in Nigella sativa seeds is thymoquinone (TQ). As well as being used as food supplements, the seeds and oil are also utilized in traditional medicine to treat a variety of ailments. The purpose of this investigation was to determine whether TQ could protect rats from acute nephrotoxicity caused by diazinon (DZN). Six equal groups of thirty six adult male Wistar rats were created at random. Group 1 (G1) was maintained in typical control circumstances and given saline daily intragastric (IG) for 4 weeks; G2 was administered 0.1 mL olive oil IG for 4 weeks; G3 was administered 0.1 mL DMSO IG for 4 weeks; G4 was administered IG TQ at a dose of 10 mg/kg B.W. daily for 4 weeks; G5 was administered IG DZN at a dose of 15 mg/kg B.W. daily for 4 weeks; G6 was administered TQ intragastric (IG) daily, one hour before DZN at the same dose as in G4 and G5, for 4 weeks. The findings showed that TQ reduces the renal dysfunctions brought on by DZN by restoring urea and creatinine levels as well as oxidative indicators. Although the expression of Kelch-like ECH-associated protein 1 (Keap1) was also elevated, overexpression of nuclear factor erythroid 2–related factor 2 (Nrf2) also enhanced the expression of heme oxygenase-1 (HO1), and Nuclear factor kappa B (NFκB) in renal tissue. Also, TQ increased antiapoptotic (BCL2) factors and decrease proapoptotic (BAX) factors. In conclusion, TQ is helpful in the prevention and management of acute nephrotoxicity brought on by DZN.