Silymarin (Sm) is widely used in treating diseases that affect organs such as the liver, kidney, and gallbladder thanks to its antioxidative, renoprotective, antihepatotoxic, and anticarcinogenic properties. However, this substance is poorly solved in water and tends to decompose in the intestine, its bioavailability decreasing before it can show real effect. With these limitations in mind, the present study aims to enhance the poor bioavailability of Sm by forming Sm-loaded solid lipid nanoparticles (Sm-SLNs) using the hot homogenization method. A characterization process was undertaken to determine possible impact of Sm on experimental kidney damage. Our biochemical and light microscopic results suggest that the group that received Sm-SLNs for the treatment of D-GalN/TNF-alpha-induced experimental kidney damage showed significantly more improvement than the group that received commercially available Sm. In conclusion, Sm-loaded SLN may be a useful system for the delivery of poorly water-soluble Sm and may also provide renoprotection.