Plant pathogenic fungi release cell wall-degrading enzymes (CWDEs), which are significant weapons for breaking down plant cell walls, although only a few reports focus on their pathogenesis. The current study demonstrates that MoFco1, a conserved α-L-fucosidase in several pathogenic fungi, degrades the hemicellulose component XXFG and contributes to the pathogenicity of Magnaporthe oryzae. In addition, MoFco1 enzyme activity is essential for its pathogenic function, as the enzyme activity mutation induced pathogenesis defects identical to the ΔMofco1 mutant. We further performed a structure-based virtual screening targeting MoFco1 and discovered 0989, which binds to MoFco1 and effectively inhibits M. oryzae pathogenesis. In brief, our study reveals the pathogenic mechanism of MoFco1 and explored the application of structure-based virtual screening in plant protection.