Four simple, precise, accurate, and eco-friendly spectrophotometric methods manipulating ratio spectra were used for the determination of acefylline piperazine (AC) and bromhexine hydrochloride (BR) in the presence of two dosage form additives — methylparaben (MP) and propylparaben (PP). The dual wavelength in ratio spectra (DWRS) and derivative of double divisor of ratio spectra (DD-RS) methods were used for the simultaneous determination of AC and BR. The first derivative ratio zero crossing method (1DD) was used for the determination of BR. AC can be determined using sequential spectrophotometry, where the ratio subtraction method was applied to remove the extended spectrum of BR followed by applying the dual wave length method. The linearity of the proposed methods was investigated in the ranges 5.00–60.00 and 4.00–60.00 μg/mL for AC and BR, respectively. The selectivity of the developed methods was investigated by analyzing laboratory-prepared mixtures containing different ratios of the cited drugs and additives in addition to the analysis of their pharmaceutical dosage form. The validity of the proposed methods was further assessed using the standard addition technique. The obtained results were statistically compared with those obtained by the reported method, showing no significant difference with respect to their accuracy and precision at p = 0.05.