Incidence of hepatocellular carcinoma (HCC) has increased sharply in the last 10 years, with an especially high incidence in Egypt. This study was conducted to evaluate the impact of unbalanced diets on liver tumor through investigation of some biochemical mediators/pathways implicated in the pathogenesis of HCC. Male albino mice were divided into two major groups: Control group and Hepatocellular carcinoma (HCC) group; each group was further divided into four subgroups according to received diet: high fat (HF), low fat (LF), high carbohydrate (HC), and low carbohydrate (LC) groups. The results indicated that induction of HCC in mice showed marked body weight loss. Liver sections of HCC groups showed malignant giant cells and strong expression of p53. HCC mice groups kept on HF and LC diets showed the lowest survival rate, a significant increase in glucose-6-phosphate dehydrogenase (G6PDH), aldolase, and citrate synthase activities, a significant increase in serum E-cadherin as well as a significant decrease in insulin-like growth factor-1 (IGF-1) compared with LF diet. These results suggest that the molecular pathogenesis of HCC in mice correlates reduction of serum IGF-1 and elevated serum E-cadherin accompanied by reprogrammed metabolic profile shifted towards increased glycolysis and lipogenesis. These pathogenic changes were enhanced by over-consumption of carbohydrates, fats, and proteins, whereas dietary fat restriction could have a protective/ameliorative effect against the incidence of HCC.