A highly validated and selective high-performance thin-layer chromatography (HPTLC) method was developed for the determination of cetirizine dihydrochloride (CET) with pseudoephedrine (PSE) and/or phenylpropanolamine (PPA) and paracetamol (PAR) in their pharmaceutical formulations. The proposed method was based on HPTLC separation of the drugs followed by densitometric measurements of their spots at 257 nm. Separation was carried out on Merck HPTLC aluminum sheets of silica gel 60 F254 using methanol-distilled water (9.95:0.05, v/v) as mobile phase. The linear regression analysis data were used for the regression line in the range of 1–4, 3–10, 4–8, and 5–100 µg band−1 for CET, PSE, PPA, and PAR, respectively. The proposed method was validated and successfully applied for the analysis of pharmaceutical formulations and laboratory-prepared mixtures containing the two multicomponent combinations. The method is validated and showed good performances in terms of linearity, sensitivity, precision, accuracy, and stability.