The edible mushroom Lentinula edodes (shiitake) contains many bioactive compounds. In the present study, we cultivated L. edodes mycelia in solid medium and examined the hot-water extract (L.E.M.) for its suppressive effect on concanavalin A (ConA)-induced liver injury in mice. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. The intraperitoneal administration of L.E.M. significantly decreased the levels of the transaminases. L.E.M. contains many bioactive substances, including polysaccharides and glucan, which could be immunomodulators. Since ConA-induced liver injury is caused by the activation of T cells, immunomodulating substances might be responsible for the suppressive effect of L.E.M. L.E.M. also contains phenolic compounds that are produced from lignocellulose by mycelia-derived enzymes. The major phenolics in L.E.M., syringic acid and vanillic acid, were intraperitoneally injected into mice shortly before the ConA treatment. Similar to L.E.M., the administration of syringic acid or vanillic acid significantly decreased the transaminase activity and suppressed the disorganization of the hepatic sinusoids. In addition, the inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-6 in the serum increased rapidly, within 3 h of the ConA administration, but the administration of syringic acid or vanillic acid significantly suppressed the cytokine levels. Together, these findings indicate that the phenolic compounds in L.E.M. are hepatoprotective through their suppression of immune-mediated liver inflammation.