Understanding the mechanism of action of antifungal drugs is vital for better control of mycosis, which kills >1.3 million lives every year thus remains a major health problem worldwide. In this study, we investigate the activities of three different categories of plant-derived antifungal compounds (resveratrol, honokiol and osthole) via transcriptomics and bioinformatics analysis, with the goal of discovering the common Mode-of-Action (MoA) at molecular level. The result shows that a common transcriptional response (72 gene are up-regulated while 10 genes are down-regulated, commonly) are triggered by above representative antifungal compounds in Schizosaccharomyces pombe (S. pombe) yeast. By virtue of gene set enrichment analysis (GSEA) and gene functional annotation study, we identify that the genes involved in oxidative stress response, sugar metabolism, fatty acid metabolism, amino acid metabolism and glycolysis are significantly up-regulated, while the genes involved in nucleosome assembly, transcription and RNA processing are down-regulated, by any of these antifungal compounds. These observations demonstrate that the common MoA includes a strengthened anti-oxidative cell adaptation, a faster metabolic rate and a generally suppressed gene transcriptional activity. It implies a genetically encoded common redistribution of intracellular energy flux and molecules synthesis, after the challenging of antifungal compounds.