Titanium dioxide nanoparticles (TiO₂-NPs) are widely utilized in cosmetics, food, and paintings. Although TiO₂-NPs may cause toxicity through a variety of routes, oxidative stress is by far the most common. Ginseng is employed in a variety of medical applications because of its potency as an antioxidant. Thus, the purpose of this study is to assess the protective and therapeutic benefits of Panax ginseng against TiO₂-NPs administration in the kidneys of male rats. Thirty-five mature male albino rats were divided into five groups of seven rats each at random. The experimental groups were as follows: Group I served as the control group; Group II received 200 mg/kg of ginseng orally; Group III received 200 mg/kg of TiO₂-NPs orally; Group IV served as the protective group;rats were pretreated with ginseng 1 hour before TiO₂-NPs at a dose similar to GII and GIII, respectively; and Group V served as the treatment group; rats received TiO₂-NPs for 14 days, then ginseng for another 14 days at a dose identical to GIII and GII, respectively. After 4 weeks, serum samples were collected, and kidney tissues were dissected for biochemical and histopathological examinations. Treatment with TiO₂-NPs elevated malonaldehyde (MDA), kidney biomarkers, and reduced glutathione (GSH) and glutathione peroxidase (GPx) levels. Furthermore, TiO₂-NPs induce upregulation of cysteine-aspartic acid protease (caspase3) and cyclooxygenase (COX-2). Histopathologically, TiO₂-NPs caused degenerative changes in renal tissue, including renal corpuscles, and showed hypertrophy with capillary congestion. Most renal tubules showed marked luminal dilation with epithelial cell flattening. Additionally, there was reduced immunoreactivity of Ki-67 in the kidney sections. Ginseng, on the other hand, substantially mitigated the detrimental impacts that TiO₂-NPs had on the rat renal tissues by down-regulating the genes for COX-2 and caspase3, restoring these biochemical and molecular parameters, and ameliorating the histological changes. In conclusion, ginseng could potentially be used to alleviate the renal toxicity brought on by TiO₂-NPs.