Citrullus colocynthis had been widely used for its reported biological activities in indigenous system of medicine. The present investigation was carried out to find the effect of different phlogistic agents-induced paw edema and carrageenan-induced air-pouch inflammation in rats. Methanol extract of Citrullus colocynthis significantly inhibited carrageenan, serotonin and prostaglandin E1-induced paw edema. Maximum inhibition was observed in prostaglandin E1-induced paw edema. In carrageenan air-pouch model, methanol extract of Citrullus colocynthis significantly reduced the volume of exudate and migration of neutrophils and monocytes. The extract significantly decreased formation of granuloma tissue in chronic inflammation model. Hence, present investigation established some pharmacological evidences to support the Citrullus colocynthis is used as anti-inflammatory agent.