A simple and sensitive Ultra Performance Liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous estimation of two Selective Serotonin and Nor Epinephrine Reuptake Inhibitors (Duloxetine &Venlafaxine) and one Selective Serotonin Reuptake Inhibitor (Paroxetine) in human plasma using Sertraline as an internal standard. The above mentioned compounds and the internal standard were extracted from 0.5 ml plasma by solid phase extraction method. The analytical separation was carried out in a reverse liquid chromatography at acidic pH 3.9 at isocratic mode. All analytes were monitored in multiple reaction monitoring mode using the respective [M+H] +ions, m/z 298.06/153.90 for Duloxetine, 279.20/57.75 for Venlafaxine,330.61/162.83 for Paroxetine and m/z 306.14/158.71 for the internal standard. The proposed method was validated with linear range of 0.5 -100ng/ml for Duloxetine, Venlafaxine and Paroxetine. The %R.S.D of intraday and inter-day assay was lower than 15%. For its sensitivity and reliability, the proposed method is particularly suitable for pharmacokinetic studies.