Different signal-transforming algorithms were applied for UV spectrophotometric analysis of paracetamol, ibuprofen, and caffeine in ternary mixtures. Phosphate buffer pH 7.2 was used as the spectrophotometric solvent. Severe overlapping spectra could be resolved into individual bands in the range of wavelengths 200–300 nm by using Savitzky–Golay smoothing and differentiation, trigonometric Fourier series, and mother wavelet functions (i.e., sym6, haar, coif3, and mexh). To optimize spectral recoveries, the concentration of various types of divisors (single, double, and successive) was tested. The developed spectrophotometric methods showed linearity over the ranges 20–40 mg/L for paracetamol, 12–32 mg/L for ibuprofen, and 1–3.5 mg/L for caffeine (R2 > 0.990). They could be successfully applied to the assay and dissolution test of paracetamol, ibuprofen, and caffeine in their combined tablets and capsules, with accuracy (99.1–101.5% recovery) and precision (RSD < 2%). For comparison, an isocratic RP-HPLC analysis was also developed and validated on an Agilent ZORBAX Eclipse XDB–C18 (150 × 4.6 mm, 5 µm) at an ambient temperature. A mixture of methanol : phosphate buffer 0.01 M pH 3 (30 : 70 v/v) was used as the mobile phase delivered at 2 mL/min, and the effluent was monitored at 225 nm. It was shown that spectrophotometric data were statistically comparable to HPLC p>0.05, suggesting possible interchange between UV spectrophotometric and HPLC methods for routine analysis of paracetamol, ibuprofen, and caffeine in their solid pharmaceutical dosage forms.