Zinc oxide eugenol (ZOE) is one of the most commonly used root canal sealer. However, it has few drawbacks such as cytotoxicity, solubility, and irritation to periapical tissues. The scope of this study was to investigate the setting time, solubility, cytotoxic effects, and anti-inflammatory action of ZOE sealer with the modification of its liquid component by the addition of petasin extract in the ratios 1:1, 5:1, and 10:1.Setting time was evaluated using the Vicat's apparatus. For testing solubility, the American Dental Association's specification #8 was adopted with certain modifications. Protein denaturation assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay with L929 mouse fibroblast cell lines were used to evaluate the anti-inflammatory property and cytotoxicity, respectively.ZOE sealer with petasin extract in the ratio of 5:1 showed the least initial and the final setting times. There was no statistically significant difference in the amount of solubility for all the groups at the various time intervals. The cytotoxicity of the control group was significantly greater than all the experimental groups, whereas the anti-inflammatory effect of the former was statistically lower.The combination of ZOE with petasin extract in the ratio of 5:1 showed lower setting time, cytotoxicity, and better anti-inflammatory property.