A selective, new, rapid and nondestructive Fourier transform Infrared spectroscopic assay has been developed for simultaneous determination of Memantine hydrochloride and Amisulpride in human plasma and their pharmaceutical formulations without interference from common dugs excipients. A binary mixture of ME and nonselective β-blocker namely; carvidalol has been determined the solid-state by FTIR spectroscopy for the first time. The linear range had been extent from 1.0 to 8.0 and 1.0 to 10.0 μg/mg, for ME and AMS respectively. The detection limits were 0.29 and 0.23 μg/mg while quantitation limits were 0.90 and 0.71 μg/mg for ME and AMS respectively. The developed assay has been validated according to ICH & USP recommendations and successfully applied for quantitative determination of selected drugs in biological fluid.