Background: Ovarian cancer, a formidable threat to women's health, is characterized by its high prevalence and the challenges associated with its diagnosis and treatment. As one of the leading causes of gynecological cancer-related mortality, ovarian cancer necessitates novel therapeutic approaches that address its aggressive nature and limited treatment options. Our study aimed to elucidate the binding affinity and conformational aspects of OPCML with natural inhibitors, offering a comprehensive understanding of their potential therapeutic impact. Methods: Molecular docking simulations were performed to assess the binding energies and interactions within the active site of the OPCML receptor complex. Ligands, such as orientin, were selected based on their diverse chemical properties and structural characteristics. Computational analyses involved a comprehensive approach, considering the potential therapeutic impact of each ligand. Results: Orientin performed as a standout candidate, displaying the best affinity binding with the lowest energy within the OPCML receptor complex's active site. The favorable binding energy indicates a robust and stable interaction with the receptor, showcasing orientin's potential as an effective OPCML ligand. However, the computational nature of molecular docking necessitates cautious interpretation, emphasizing the need for further experimental validations. Conclusion: While orientin demonstrates promising affinity binding, further in vitro and in vivo studies are essential to confirm its actual binding activity with OPCML and assess its translational potential as a therapeutic agent. The diverse set of ligands provides a comprehensive overview of potential OPCML ligands, underscoring the importance of a broad screening approach in drug discovery. The identification of orientin as the lead candidate emphasizes the significance of such an approach. This molecular docking study opens avenues for further research into orientin's mechanisms of action and therapeutic efficacy, laying the groundwork for targeted experimental validations that advance our understanding of orientin as a potential OPCML ligand with biological and therapeutic relevance.