Induced biosynthesis of bioactive secondary metabolites constitutes one of the mechanisms of plant basal innate immunity to fungal infection. Metabolic changes were studied in rhizomes of Zingiber zerumbet, a wild congener of ginger, after infection with soft rot-causative necrotrophic phytopathogen, Pythium myriotylum, by gas chromatography-mass spectrometry (GC-MS) analysis. Infection triggered a considerable alteration in the relative content of zerumbone and α-caryophyllene (humulene) with enhancement in zerumbone content (81.59%) and that of α-caryophyllene (11.91%) compared to 9.97 and 1.11%, respectively, in uninfected rhizomes. While zerumbone is the principal secondary metabolite in Z. zerumbet, α-caryophyllene is its immediate precursor. Principal component analysis (PCA) identified the correlations between metabolite changes in Z. zerumbet rhizomes and P. myriotylum infection. Radial diffusion assay with zerumbone indicated a concentration-dependent P. myriotylum growth inhibition with 93.75% inhibition observed at 700 μg and 50% maximal effective concentration (EC50) value of 206 μg. Scanning electron microscopy (SEM) analysis revealed that the mechanistic basis of zerumbone's antagonistic action on P. myriotylum growth involved the induction of aberrant morphology including severe hyphal deformities and membrane disruption. Results are discussed highlighting the critical role played by sesquiterpenoid zerumbone in affording resistance in Z. zerumbet and could expedite the development of appropriate strategies for biocontrol of Pythium spp., thus reducing the usage of broad-spectrum fungicides.