The analytical performance of cumulative area pre-processing (CAP), a recently developed signal filtering method, along with multivariate calibration for quantification of spectrally overlying drugs was outlined. The drug combinations containing high level of paracetamol (PAR) in the presence of caffeine (CAF), chlorpheniramine maleate (CHL), pseudoephedrine hydrochloride (PSE), phenylephrine hydrochloride (PHE), and diphenhydramine hydrochloride (DPH). The tested formulations were: PAR-CAF-PHE, PAR-CAF-PHE, and PAR-DRH. Based on netanalyte signal calculations, the formulations exhibited intense overlapping 53-68% for PAR-PSE-CHL, 55-95% for PAR-CAF-PHE, and 44% for PAR-DRH. For each system, PLS latent variables were estimated using cross-validation technique and more factors were needed for highly overlapping systems. PLS-CAP was found applicable for drugs quantification in all systems with excellent performance regardless the size of spectral overlapping and ratios of components in the formulation. For PAR-PSE-CHL (ratio 300:30:2 mg/tablet), the ingredients were quantified by CAP-PLS with satisfactorily recoveries (RSD, n = 3) 89.9% (3.1%), 104.6% (2.7%), and 99.0% (1.5%) for PAR, PSE, and CHL, respectively. Both PLS and CAP-PLS were demonstrated the same performance for binary system of modest overlapping and no component available in low concentration.