Background: Thrombo-embolic disorders are one of the major causes of 'morbidities and mortality' worldwide. Antithrombotic therapy which comprise use of anti-platelet agents, fibrinolytic agents and anti-coagulants seem to be ineffective in the treatment of thrombi due to side effects and delayed onset of effects, along with chances of hemorrhage. Euphorbia neriifolia Linn is a large succulent shrub, with stipular thorns and is found throughout the Deccan peninsula of India. The plant is known for its medicinal value. A number of evidence about resins and flavonoids has demonstrated potent antithrombotic effects in vitro and in vivo due to prevention of the actions of 'cyclooxygenase and lipoxygenase pathways'. Aim: The present work was designed study antithrombotic potential of this E. neriifolia Linn. Materials and Methods: The whole plant of E. neriifolia Linn were shade dried at 37 o C to 40 o C and coarsely powdered through mesh 20. Powder was defatted with petroleum ether and extracted with ethanol by soxhlet apparatus and subjected to phytochemical analysis. Acute toxicity of extract was determined by Organization for Economic Cooperation and Development guideline No 423. Carrageenan-induced rat tail thrombosis model was used to study the anti-thrombotic effect by measuring thrombosis of tail and bleeding time as well as clotting time. Result: The extract was found to be rich in flavonoids, polyphenols, alkaloids, tannins and resins. Swelling and redness were observed within 2-3 h after intravenous injection of carrageenan, and the tail appeared auburn after 6 h, indicating that thrombosis had formed in the tail. Extract significantly (*P < 0.05, **P < 0.01) increased the bleeding and clotting time of the animals subjected to the test. Discussion and Conclusion: In the present work, phyto-constituents like flavonoids and polyphenols could be responsible to demonstrate protective effect on experimentally induced thrombosis in murine model.