Non-alcoholic steatohepatitis (NASH), especially as part of the metabolic syndrome (MS), is an increasing burden in western countries. Statins are already used in metabolic syndrome and seem to be beneficial in liver diseases. The aim of this study was to investigate the molecular mechanisms underlying pleiotropic effects on small GTPases of statins in NASH. NASH within MS was induced in 12-week-old ApoE-/- mice after 7 weeks of western diet (NASH mice). Small GTPases were inhibited by activated simvastatin (SMV), NSC23766 (NSC) or Clostridium sordellii lethal toxin (LT) using subcutaneous osmotic mini-pumps. Hepatic steatosis, inflammation and fibrosis were assessed by histology, Western blot and RT-PCR, measurements of cholesterol and hydroxyproline content. SMV treatment significantly decreased hepatic inflammation and fibrosis, but had no significant effect on steatosis and hepatic cholesterol content in NASH. SMV blunted fibrosis due to inhibition of both RhoA/Rho-kinase and Ras/ERK pathways. Interestingly, inhibition of RAC1 and Ras (by LT) failed to decrease fibrosis to the same extent. Inhibition of RAC1 (by NSC) showed no significant effect at all. Inhibition of RhoA and Ras downstream signaling by statins is responsible for the beneficial hepatic effects in NASH.