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<i>Background and Objective</i>: There is increasing interest in preventing periodontitis using natural products. The purpose of this study was to investigate the effect of <i>Colocasia antiquorum</i> var. <i>esculenta</i> (CA) varnish on the oral microbiome and alveolar bone loss in a mouse periodontitis model. <i>Materials and Methods</i>: Antibacterial activity against <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) ATCC 53978 and cell cytotoxicity using CCK-8 on L929 cells were measured. Balb/c mice were assigned into five groups (negative control, positive control, CA in drinking water, varnish, and CA varnish). <i>P. gingivalis</i> was administered to the mice by oral gavage three times. After sacrifice, the oral microbiome and the levels of the inflammatory cytokine IL-1β and matrix metalloproteinase-9 were analyzed. Alveolar bone loss was measured using micro-computed tomography. <i>Results</i>: CA extract showed an antibacterial effect against <i>P. gingivalis</i> (<i>p</i> < 0.05) and showed no cytotoxicity at that concentration (<i>p</i> > 0.05). Although alpha diversity of the oral microbiome did not statistically differ between the groups (<i>p</i> > 0.05), the relative abundance of dominant bacteria tended to be different between the groups. The inflammatory cytokine IL-1β was reduced in the CA varnish group (<i>p</i> < 0.05), and no difference was observed in MMP-9 expression and alveolar bone loss (<i>p</i> > 0.05). <i>Conclusions</i>: CA varnish did not affect the overall microflora and exhibited an anti-inflammatory effect, suggesting that it is possibility a suitable candidate for improving periodontitis.