The present study aimed at assessing the protective effect of water extract from fruit body of the Grifola frondosa (GFW) on carbon tetrachloride ($CCl_4$)-induced hepatotoxicity. Rats orally administered with GFW 0.5, 1.0, 2.0 g/kg for 14 days were treated with $CCl_4$ to induce hepatotoxicity. Pretreatment with GFW remarkably prevented the elevation of serum AST, ALT, ALP, LDH, $gamma$-GTP, and liver lipid peroxides in $CCl_4$-treated rat and GFW administration in liver injured rats by $CCl_4$ showed significant (p<0.05) protection of liver as evidenced from normal serum enzymes and malondialdehyde (MDA) levels. In the ultrastructural changes, administration of $CCl_4$-induced damage of hepatocytes with vacuolation, a highly damaged endoplasmic reticulum, and degenerating nuclei. However, pre-administration with GFW preserved normal ultrastructure of hepatocytes. These results suggest that GFW had an effect to inhibit $CCl_4$-induced liver injury in rat, and that it could be used as an effective hepatoprotective agent against chemical-induced liver damage.