The Lingzhi or Reishi mushroom Ganoderma lucidum is a well-known traditional medicinal mushroom that has been shown to have obvious hepatoprotective effects. The aim of this study was to evaluate the hepatoprotective effects of G. lucidum aqueous extracts (GLEs) on liver injury induced by α-amanitin (α-AMA) in mice and to analyze the possible hepatoprotective mechanisms related to radical scavenging activity. Mice were treated with α-AMA prepared from Amanita exitialis and then administrated with GLE after the α-AMA injection. The hepatoprotective activity of the GLE was compared with the reference drug silibinin (SIL). α-AMA induced a significant elevation in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and provoked a significant reduction of superoxide dismutase (SOD) and catalase (CAT) activities and a significant increment of malondialdehyde (MDA) content in liver homogenate. Treatment with GLE or SIL significantly decreased serum ALT and AST levels, significantly increased SOD and CAT activities, and decreased MDA content in liver compared with the α-AMA control group. The histopathological examination of liver sections was consistent with that of biochemical parameters. The results demonstrated that GLE induces hepatoprotective effects on acute liver injury induced by α-AMA; these protective effects may be related in part to the antioxidant properties of GLE.