Three methods are developed for the simultaneous determination of theophylline anhydrous (TH), guaiphenesin (GP), diphenhydramine hydrochloride (DP), methylparaben (MP), propylparaben (PP) and sodium benzoate (BZ) in pharmaceutical syrup. The chromatographic method depends on a high performance liquid chromatographic separation on a reversed-phase C18 column at ambient temperature with mobile phase consisting of 25 mM KH2PO4, pH 3.2—acetonitrile (60:40, v/v). Quantitation was achieved with UV detection at 222 nm based on peak area. 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 six components in the studied mixture using information included in the UV absorption spectra of appropriate solutions in the wavelength range of 220–270 nm with Δλ = 0.4 nm. The calibration PLS-1 and PCR models were 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 over synthetic and pharmaceutical preparation. The results of PLS-1 and PCR methods were compared with the HPLC method and a good agreement was found.