Plant-derived small molecules play a crucial role in defending against pathogenic organisms. Leveraging cutting-edge technologies such as AlphaFold2 and diffusion model-based DiffDock, this study investigated the potential of these molecules for antifungal activity, specifically targeting Fusarium oxysporum, the causative agent of potato dry rot. Through gene family analysis, we identified 15 putative antifungal target proteins and accurately predicted their structures using AlphaFold2. To model the interaction patterns between these proteins and plant-derived compounds, we utilized the DiffDock with a diffusion model-based algorithm, generating complex interactions for each of the 1,453 small molecules. A thorough evaluation of over 200,000 interaction models resulted in the identification of small molecules displaying significant antifungal activity. To further validate our findings, we used AlphaFold3 to confirm the interaction sites predicted by AlphaFold2, achieving consistent results that verify our predictions. Experimental validation showed that coumarin inhibits F. oxysporum, likely by disrupting cell wall synthesis. GSEA analysis of transcriptomic data confirmed that coumarin affects the chitin synthase pathway, inhibiting F. oxysporum growth. In summary, this study highlighted the efficacy of AlphaFold2, AlphaFold3, and DiffDock in predicting protein structures and small molecule-protein interactions, demonstrating the potential of artificial intelligence-driven approaches in uncovering new antifungal strategies.