The fast growing evidences have shown that the plant-derived compound honokiol is a promising candidate for treating multiple human diseases, such as inflammation and cancer. However, the mode-of-action (MoA) of honokiol remains largely unclear. Here, we studied the antifungal activity of honokiol in fission yeast model, with the goal of understanding the honokiol's mechanism of action from the molecular level. We found that honokiol can inhibit the yeast growth at a dose-dependent way. Microarray analysis showed that honokiol has wide impacts on the fission yeast transcription levels (in total, 512 genes are up-regulated, and 42 genes are down-regulated). Gene set enrichment analysis indicated that over 45% up-regulated genes belong to the core environmental stress responses category. Moreover, network analysis suggested that there are extensive gene-gene interactions amongst the co-expression gene lists, which can assemble several biofunctionally important modules. It is noteworthy that several key components of central carbon metabolism, such as glucose transporters and metabolic enzymes of glycolysis, are involved in honokiol's MoA. The complexity of the honokiol's MoA displayed in previous studies and this work demonstrates that multiple omics approaches and bioinformatics tools should be applied together to achieve the complete scenario of honokiol's antifungal function.