Ephrin type-A receptor 1 (EphA1) is a receptor tyrosine kinase implicated in tumor progression, angiogenesis, metastasis, and immune regulation, making it an attractive therapeutic target in cancer. In the present study, a structure-based virtual screening approach was employed to identify potential natural inhibitors of EphA1. A library of 90,000 natural compounds retrieved from the ZINC database was filtered using Lipinski’s rule of five, yielding 32,901 drug-like molecules for docking analysis. The three-dimensional structure of EphA1 was obtained from the AlphaFold database, and molecular docking was performed using InstaDock. Based on binding affinity scores (-11.2 to -9.4 kcal/mol), the top 320 compounds were shortlisted and further subjected to PAINS filtering, physicochemical evaluation, ADMET prediction, carcinogenicity assessment, and PASS analysis. Two compounds, ZINC12660859 and ZINC12661003, demonstrated favourable drug-likeness, high gastrointestinal absorption, non-carcinogenicity, and predicted antineoplastic activity. Interaction analysis revealed that these compounds bind within the ATP-binding pocket of the kinase domain, forming key interactions with residues such as Lys656 and Asp749. Molecular dynamics simulations over 100 ns of the EphA1–ZINC12660859 complex confirmed structural stability, with stable RMSD (0.26 nm), consistent radius of gyration (1.93 nm), minimal SASA variation, and sustained hydrogen bonding throughout the simulation. Overall, ZINC12660859 exhibited strong binding affinity and dynamic stability, suggesting its potential as a lead candidate for EphA1-targeted anticancer therapeutics.