Spectrophotometric and high-performance liquid chromatographic (HPLC) methods are developed for simultaneous determination of three binary mixtures with overlapping spectra. The spectrophotometric method is based on the use of second derivative of the ratio spectra (2DD) for resolution of three binary mixtures of indapamide with captopril (mixture 1), cinnarizine with heptaminol acefylline (mixture 2) and amoxycillin trihydrate with flucloxacillin sodium (mixture 3). The HPLC method depends on the separation of components of binary mixtures using ODS column with mobile phase consisting of acetonitrile and 5 mM aqueous heptane sulphonic acid sodium salt in ratios of (60:40, v/v, pH 5.5) for mixture 1, (50:50, v/v, pH 3.0) for mixture 2 and (35:65, v/v, pH 4.2) for mixture 3. The proposed methods are accurate, non-destructive and successfully applied for the determination of the three binary combinations in synthetic mixtures and commercial pharmaceutical products.