Nonalcoholic steatohepatitis (NASH) is becoming the most common cause of hepatocellular carcinoma (HCC) in developed countries. Oxidative stress plays a major role in the pathogenesis of NASH due to steatosis; hence, novel therapeutic approaches might include natural antioxidants. Ceraceomyces tessulatus strain Basidiomycetes-X (BDM-X), a novel edible mushroom, possesses potent antioxidant activity. This study aimed to investigate the hepato-protective effect of C. tessulatus BDM-X in a novel NASH-HCC mouse model. To prepare this animal model, 2-day-old C57BL/6J male pups were exposed to low-dose streptozotocin (STZ); at 4 weeks of age, they were randomly divided into two groups. The NASH group (NASH) received a high-fat diet (HFD32) up to 14 weeks of age; the C. tessulatus BDM-X group (BDM-X) received HFD32 up to age 10 weeks, followed by HFD32 + 20% BDM-X (percent weight per weight in the diet) up to age 14 weeks. Mice not treated with STZ and fed a normal diet served as a control group. We found that C. tessulatus BDM-X improved serum aminotransferase levels as well as histopathological features such as steatosis, inflammatory foci, and pericellular fibrosis in NASH mice. Hepatic protein expression of sterol regulatory element binding protein isoform SREBP-1 and peroxisome proliferator-activated receptor PPARα was significantly increased in NASH mice. C. tessulatus BDM-X treatment normalized the expression of both proteins. Our data suggest that C. tessulatus BDM-X may protect the liver against lipogenesis in NASH-HCC mice.