Abstract A common and efficient analgesic-antipyretic medication for a variety of syndromes is paracetamol (PAR). The use of PAR was associated with acute kidney injury and other side effects, and its hazardous effects were influenced by oxidative stress and inflammation. Black seed oil’s primary active ingredient, thymoquinone (TQ), has anti-inflammatory, immunomodulatory, and antioxidant properties. A few animal models for drug-induced nephrotoxicity described promising outcomes of its renoprotective action. The main goal of this work was to evaluate TQ nanoparticles’ (TQNP) powerful renoprotective properties in a rat model of nephrotoxicity caused by PAR. Three groups of eight rats each were assigned; group one (the control group, CON) was given gavaged normal saline. Group 2 (PAR group, PAR) received 600 mg/kg of gavaged PAR diluted in regular saline. One hour after PAR delivery, group 3 (the TQNP group) received TQNP 0.5 mg/kg via oral administration. In rat kidney tissues, PAR resulted in renal damage, a rise in blood urea nitrogen (BUN), creatinine, cystatin C (CYC), myeloperoxidase, protein carbonyl (PC), malondialdehyde (MDA), and a decrease in nitric oxide and cellular antioxidants. In rats given PAR, TQNP effectively reduced renal damage, lowered serum levels of creatinine, BUN, and CYC, and improved oxidative stress (MDA, MYO, and PC) and inflammatory markers (TNFα and IFN-γ). TQNP treatment resulted in modestly dilated/congested blood vessels in the renal tissues of PAR. The TQNP’s renoprotective action is an effective preventative against PAR-induced nephrotoxicity, primarily by enhancing cellular defense mechanisms and reducing inflammatory and oxidative indicators in a rat model. However, additional research and clinical trials should be needed for testing in future studies.