As a toxic heavy metal, lead (Pb) is well known for impairment of renal function due to oxidative injuries. In contrast, the antioxidant activity of silibinin has been approved. Given the role of silibinin antioxidant activity, the present study investigated the effectiveness of silibinin-loaded nanostructured lipid carriers (Sili-NLCs) against Pb-induced acute nephrotoxicity in rats. The emulsification-solvent evaporation method was applied to prepare Sili-NLCs. Sixty male Wistar rats were divided into ten separate groups. Pb (20 mg/kg/day, i.p.) was applied to induce nephrotoxicity and in the treatment groups animals received the same concentration of silibinin and Sili-NLCs (25, 50, and 100 mg/kg/day, p.o.) for five days. After sacrificing rats, kidney tissue samples were collected to assess the oxidative stress parameters, including lipid peroxidation (LPO), nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity. Also, histopathological examination using Hematoxylin-Eosin (H&E) was studied. Not only did Pb injection significantly increase the renal levels of LPO and NO, but also decreased the levels of antioxidant enzyme activity. On the other hand, Sili-NLCs were more effective than silibinin in decreasing renal oxidative damage by increasing the antioxidant defense system. Moreover, the histopathological examination correlated well with biochemical findings. Our data suggested that Sili-NLCs are potentially superior to pure silibinin for attenuating Pb-induced acute nephrotoxicity.