High-performance liquid chromatography (HPLC) and multivariate spectrophotometric methods were developed for the simultaneous determination of allobarbital (ALO), adiphenine hydrochloride (ADI), and paracetamol (PAR) in suppository medication. The HPLC method was performed on a C18 column with a mobile phase consisting of a mixture of acetonitrile and buffer solution (pH 4.0) of sodium acetate and acetic acid (60:40, v/v) and UV detection at 195nm. This method was validated for its linearity, precision, accuracy, and robustness. Also, the resolution of three components has been accomplished by using the multivariate calibration methods PCR and PLS-2. Experimental calibration matrix was constructed using 27 samples, according to the 3(3) full factorial design. These chemometric methods were tested by analyzing the synthetic mixtures of three drugs. The proposed methods were succesfully applied for the analysis of pharmaceutical formulations containing ALO, ADI, and PAR combinations and the obtained results were statistically compared with each other.