Duloxetine Hydrochloride is a selective serotonin reuptake inhibitor used for depression. In the proposed method, duloxetine hydrochloride was determined from human plasma using LC-MS method. Liquid-Liquid extraction method was used for the estimation of duloxetine hydrochloride. The drug was found to be stable in plasma and various parameters of bioanalytical validations were executed using LC-MS as per ICH guidelines and the proposed method was found to be sensitive, selective, economic and reproducible for the estimation of duloxetine in human plasma.