Only in the last few years has non-alcoholic steatohepatitis been recognized as an important and relatively common liver disease. To date, the therapeutic options are limited, vitamin E and metformin have been proposed for the treatment of this condition, although their mechanisms are not completely clarified as yet. The aim of this study was to investigate the anti-inflammatory and anti-oxidative mechanisms of these drugs in an experimental model of non-alcoholic steatohepatitis in the young rat. Male rats, just after weaning, were divided into four groups: a control group that received a standard diet; a high fat diet group; two high fat diet fed groups treated with vitamin E or metformin, respectively. After 4 weeks, we evaluated in the liver the modification of lipid peroxidation, assessed by malondialdehyde, TNF-α levels, S-nitrosylated protein, inducible nitric oxide sinthase (iNOS), and peroxisome proliferators-activated receptors (PPAR) expression and metalloproteinase activity. High fat diet increased malondialdehyde, nitrotyrosilated proteins, and TNF-α tissue content. Moreover, a decrease of PPAR-α and an increase of PPAR-γ expression were observed. An increase of metalloproteinase activity was also shown. Among drug treatments, metformin reduced body weight gain and fat mass, metalloproteinase activity, and TNF-α tissue content, while it restored PPAR-α expression and downregulated PPAR-γ expression. Vitamin E reduced the oxidative damage, protein nitrotyrosilation, and tissue TNF-α levels. Moreover a decrease of PPAR-γ expression was also shown. These findings confirm the efficacy of both drugs as therapeutic tools in preventing the early onset of liver damage and non-alcoholic fatty liver disease progression.