Background: Cordyceps sinensis (CS), a traditional Chinese herbal medicine, has many pharmacological effects. Doxorubicin (DOX) is a spectrum antitumor drug, but it has toxicity to multiple organs. Objective: The objective of this study was to evaluate the effect of fermented CS on regulating hepatic energy metabolism against DOX-treated hepatic toxicity in rats. Materials and Methods: Male Sprague-Dawley rats were randomly divided into six groups and administrated orally for 23 days as follows: normal control group, CS (1.50 g/kg/d) control group, DOX control group, and DOX + CS (0.75 g/kg/d, 1.5 g/kg/d, 3.00 g/kg/d) groups. Rats in DOX-treated groups were intraperitoneally injected with DOX at a dose of 2.5 mg/kg at every 48 h, and repeated for six times. At the end of the experiment, the mortality and liver index, blood biomarkers about the hepatic injury, hepatic histopathological changes, hepatic energy metabolism, and hepatic cyclic adenosine monophosphate (AMP) were measured. Results: DOX-induced a higher mortality, the damage of the liver manifests itself in the increase of liver weight index and the activity of serum aspartate aminotransferase, the decrease of serum contents of total protein and albumin, and histopathological changes, and the disorders of energy metabolism including the decrease of phosphocreatine, adenosine-triphosphate, adenosine diphosphate, AMP, and total adenine nucleotides in hepatic tissues. Fermented CS not only could attenuate those changes but also could increase the content of hepatic cAMP. Conclusion: DOX induces hepatic injury accompanying hepatic energy metabolism disorders. Fermented CS regulates the disorders of hepatic energy metabolism, thereby attenuating liver injury caused by DOX.