For the development and validation of a bioanalytical approach that uses liquid chromatography tandem mass spectrometry to simultaneously measure Nebivolol, hydrochlorothiazide, Metoprolol, and amlodipine in human plasma (LC-MS),where amlodipine was used as an internal standard, a simple, rapid, sensitive, and specific method has been proposed (IS). Acetonitrile recovered the following analytes: ammonium acetate of nebivolol 142-2840ng/ml (r² value 0.9994), hydrochlorothiazide 12.1-22ng/ml (r² value 0.9993), and metoprolol 8.09-161.8ng/ml (r² value 0.9992) using amlodipine as internal standard. LOD and LOQ of nebivolol 46.86ng/ml & 142ng/ml, hydrochlorothiazide 3.4ng/ml & 12.1ng/ml and metoprolol 2.67ng/ml & 8.09ng/ml were found. Drugs were extracted by Liquid -Liquid extraction method. According to USFDA guidelines the method was established and validated.