The present study aims at examining the effects of Si-Ni-San, a prescription usually used for treating hepatitis in Traditional Chinese Medicine (TCM), on various experimental liver injury models and its mechanisms. The prescription showed significant hepatoprotection against CCl(4)-induced hepatic damage, both in vivo and in vitro. To the liver injury induced by Bacillus Calmette-Guerin (BCG) with lipopolysaccharide (LPS), Si-Ni-San also provided significant alleviation through enhancing nitric oxide (NO) release by macrophages. Against the liver injury induced by a delayed-type hypersensitivity reaction to picryl chloride (PCl-DTH), Si-Ni-San alleviated it remarkably when administered during either the induction or effector phase. A significant reduction of in-vitro hepatotoxicity, as measured by the inhibition of serum transaminase evaluation, was observed in nonparenchymal cells from liver-injured mice treated with Si-Ni-San. Si-Ni-San facilitated apoptosis in nonparenchymal cells from liver-injured mice, as well as in spleen cells activated by PCl in vivo or by Con A in vitro. These results suggest that Si-Ni-San provides alleviating effects against liver injury through multiple mechanisms, including protection of the hepatocyte membrane, enhancement of NO release, and dysfunction of liver-infiltrating cells mainly through causing their apoptosis.