Lipopolysaccharide (LPS) is a component of the cell wall of Gram-negative bacteria that produces endotoxemia, which may cause septic shock. Metformin (MET) is a widely used hypoglycemic drug that exhibits anti-inflammatory properties. Fibroblast growth factor 21 (FGF21) is an endocrine polypeptide that affects glucose and lipid metabolism, and also possesses anti-inflammatory properties. We investigated the effects of MET and FGF21 on inflammation due to LPS induced endotoxemia in male rats. Animals were divided into five groups: control, LPS, pre-MET LPS, LPS + 1 h MET and LPS + 3 h MET. Serum levels of alanine aminotransferase, aspartate aminotransferase, FGF2, interleukin-10 and tumor necrosis factor alpha were measured. Malondialdehyde, myeloperoxidase and FGF21 levels were measured in liver tissue samples. Histopathology of all groups was assessed using hematoxylin and eosin stained sections. LPS caused severe inflammatory liver damage. MET exhibited a partially protective effect and reduced inflammation significantly. FGF21 is produced in the liver following inflammation and MET may increase its production.