Introduction: Hepatocellular carcinoma (HCC) is a critical health problem that is classified as the fifth most prevalent malignancy in the world. Our study aimed to investigate the anti-tumor activity of the Egyptian cobra venom and honey bee venom in the treatment of DENA induced HCC in rats compared to the chemotherapeutic drug cisplatin. Methods: 70 male adult albino rats were randomly placed into seven groups. Group 1 served as a negative control. Group 2 received 0.1 LD50 snake venom (SV). Group 3 received 0.1 LD50 bee venom (BV). While the other four groups received diethylnitrosamine (DENA) to induce HCC, they were subsequently divided as follows: Group 4 served as a positive control group (HCC), and the other three remaining groups represented the treated groups. Group 5: snake venom-treated group (HCC+SV). Group 6: bee venom-treated group (HCC+BV). Group 7: Cisplatin-treated group (HCC+CIS). Results: DENA induced HCC, as proved by a significantly high increase in AST, ALT, GGT, and ALP activities and a decrease in total protein and albumin contents. Also, significantly elevated levels of urea, creatinine, proinflammatory cytokine (IL-1β), and tumor markers (NRP1, ANG2, TOPBP1) in comparison to the negative control group. Treatment of HCC rats using snake venom, bee venom, and cisplatin revealed a significant decrease in liver enzymes and tumor markers. The venoms showed a potent synergistic anti-tumor effect by significantly upregulating the expression of pro-apoptotic gene Caspase 3 and downregulating the expression of the anti-apoptotic gene (Bcl-2) in comparison to the positive control HCC group. Our findings were confirmed by histological analysis and immunohistochemical Caspase-3 expression. Discussion: Both snake venom and bee venom have anti-inflammatory, apoptotic, and anticancer effects against induced HCC. However, the use of BV is more effective and safer than SV. Conclusion: Egyptian cobra venom and honey bee venom may serve as an apoptotic stimulator, and can be considered as novel potential therapeutic against HCC.