Sepsis is a leading cause of death among intensive care patients. During sepsis, exaggerated reaction to infection leads to massive production of reactive oxygen species and inflammatory mediators, which eventually leads to multiple organ damage. Silymarin is a well-known antioxidant and cytoprotective agent, which showed protective effects in different models of disease. Thus, we hypothesized that silymarin would be protective against sepsis-induced liver and kidney injury. Sepsis was induced in rats by the cecal ligation and puncture (CLP) method. Rats were divided into sham, CLP-non-treated and CLP treated with silymarin (100 mg/kg, i.p. 1 h following CLP). After 24 h, rats were euthanized for blood and tissue samples, which were used for assessment of MDA, NO, GSH, IL-6 and TNF-α levels and SOD activity, in addition to renal and hepatic function parameters. Survival study was conducted using another set of animals following the same previously mentioned procedure. Silymarin showed protective effects evidenced by enhanced overall survival following sepsis (80% in silymarin-treated vs. 20% in septic group), in addition to improvement of hepatic and renal function parameters and reduction of MDA, NO, IL-6 and TNF-α levels. Moreover, silymarin supported the endogenous antioxidant mechanisms via elevation of GSH levels and reinforcement of SOD activity. In conclusion, silymarin protects against sepsis-induced hepatic and renal injury, possibly via antioxidant and anti-inflammatory mechanisms.