Aqueous and ethanol extracts of this Spilanthes calva DC is widely used in folk medicine in South India for treating various parasitic diseases. In vitro anthelmintic activities of crude aqueous and alcoholic extract of aerial parts of the plant was investigated to provide experimental evidence for its use in folk medicine. Investigations of in vitro anthelmintic efficacy were evaluated separately on adult Pheretima posthuma and Ascaridia galli compared with Albendazole. Ethanol extract showed more anthelmintic activity than aqueous extract. Six compounds were isolated from ethanol extract compounds 3, 4 and 6 showed significant anthelmintic activity with LC50 values of 12, 11, 9.9 and 11.47, 10.56, 8.35 respectively against both the worms. The oral LD50 of the aqueous and ethanol extracts estimated in mice is greater than 5000mg/kg. Molecular docking studies were carried out for compound 6 by using ArgusLab 4.0.1. and Molegrow 2012.2.5.0 generated the enzyme binding interaction which suggested the lactone ring attained a non-coplanar conformation with benzisoxazole can contribute two significant hydrogen bonding interaction with Tyr 50 and Gln 134. This could be attributed to the slight structural resemblance with Albendazole and hydrogen bonding, π-π and non-polar interactions towards the inhibitor-binding cavity of the β-tubulin enzyme. Our study shows ingredients in S. calva DC ethanol extract contains an effective anthelmintic composition that could potentially developed as a promising plant origin anthelmintic.