Three methods were developed for the determination of two ternary mixtures containing drotaverine hydrochloride (DR) with caffeine and paracetamol (mixture 1) and DR with metronidazole and diloxanide furoate (mixture 2). The first method depends on HPLC separation on an RP C18 column at ambient temperature with the mobile phase methanol-water, pH 3.1 (50 + 50, v/v) and UV detection at 213 nm for mixture 1, and the mobile phase acetonitrile-25 mM potassium dihydrogen phosphate, pH 4.6 (55 + 45, v/v) with UV detection at 235 nm for mixture 2. The other two chemometric methods applied were partial least squares (PLS-1) and principal component regression (PCR). These approaches were successfully applied to quantify the five drugs in two ternary mixtures using information included in the UV absorption spectra of appropriate solutions in the wavelength range of 210-300 nm with 1 nm intervals. Calibration of PCR and PLS-1 models was evaluated by internal validation (prediction of compounds in its own designed training set of calibration), by cross-validation (obtaining statistical parameters that show the efficiency for a calibration fit model), and by external validation (using laboratory-prepared mixtures and pharmaceutical preparations). The proposed methods were successfully applied for the determination of the two ternary combinations in laboratory-prepared mixtures and commercial tablets; the results of PLS-1 and PCR methods were compared with the HPLC method, and a good agreement was found.