<p>Lead exposure is a significant factor in the development of chronic kidney disease. This study examined the effects of the monoterpene eucalyptol on nephrotoxicity induced by lead acetate in adult male Wistar rats. The animals were divided into four groups: Control, Eucalyptol, Lead, and Lead-Eucalyptol. Over 14 days, lead acetate (25 mg/kg) and eucalyptol (100 mg/kg) were administered via gavage. The results showed that eucalyptol reduced the levels of malondialdehyde in the kidneys of rats exposed to lead acetate (p &lt; 0.05). It also increased levels of glutathione (p &lt; 0.05) and enhanced the activities of the enzymes superoxide dismutase (p &lt; 0.05) and glutathione peroxidase (p &lt; 0.01). Likewise, eucalyptol reduced the expression of proinflammatory cytokines, including tumor necrosis factor-α (p &lt; 0.01), interleukin (IL)-1 beta (p &lt; 0.001), and IL-6 (p &lt; 0.001) as well as Bax (p &lt; 0.001) and caspase-3 (p &lt; 0.001), while increasing the expression of Bcl2 (p &lt; 0.01). It elevated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) (p &lt; 0.001), thereby preventing histopathological damage. Moreover, treatment with eucalyptol resulted in a reduction in serum creatinine and blood urea nitrogen levels in rats exposed to lead acetate (p &lt; 0.001). We concluded that eucalyptol mitigates lead-induced nephrotoxicity by inhibiting oxidative stress, inflammation, and apoptosis. The renoprotective effects of eucalyptol appear to be mediated by the stimulation of the Nrf2/HO-1 signaling pathway. Therefore, eucalyptol may represent a promising option for reducing lead-induced toxicity.</p> Graphical Abstract <p></p>