Background: Hepatocellular carcinoma (HCC) poses a significant global health challenge, necessitating innovative therapeutic approaches. The human hepatoma-derived growth factor (hHDGF) has emerged as a crucial player in HCC progression, making it a potential target for inhibition. This study explores the inhibitory potential of various compounds against the hHDGF receptor complex, utilizing molecular docking simulations. Methods: A comprehensive in silico approach was employed, utilizing molecular docking simulations to assess the binding energies and interactions of compounds with the active site of hHDGF. In total of 17 ligands of natural compounds were selected based on their diverse chemical properties and structural characteristics. Comparative analyses were conducted against established compounds to identify potential lead candidates. Results: Rutin exhibited the most favorable binding energy within the active site of the hHDGF receptor complex, standing out as a lead candidate for inhibition. The superior binding energy indicates a robust interaction, suggesting rutin's potential as an effective hHDGF inhibitor. While rutin demonstrated the best binding energy, cautious interpretation is warranted, acknowledging the computational nature of molecular docking. Further experimental validations, including in vitro and in vivo studies, are essential to confirm rutin's inhibitory activity against hHDGF. Conclusion: The identification of rutin as a standout candidate underscores the significance of leveraging diverse natural compounds in drug discovery for HCC. Rutin's potential inhibitory activity against hHDGF opens avenues for further research, warranting detailed investigations into its mechanisms of action and therapeutic efficacy. The promising results of this molecular docking study pave the way for targeted experimental validations, advancing our understanding of rutin and its role as a potential inhibitor against hHDGF in the context of hepatocellular carcinoma.