Two simple and rapid spectrophotometric methods were developed for the determination of two binary mixtures: moxifloxacin hydrochloride (MFH) with ketorolac tromethamine (KTM) and ciprofloxacin hydrochloride (CFH) with dexamethasone sodium phosphate (DSP). The first method, zero-crossing derivative spectrophotometry, depends on measuring the second derivative peak and trough values at 304 nm and 250.6 nm for MFH and KTM, respectively. The second method is a derivative ratio spectrophotometry. It depends on measuring the trough amplitude of the second derivative of the ratio spectra at 287.5 nm by dividing the spectra of CFH by the spectrum of 15.0 μg mL-1 DSP. Also, DSP was determined by measuring the peak amplitude of the third derivative of the ratio spectra at 254.5 nm using 10.0 μg mL-1 CFH as the divisor. The proposed methods were validated in compliance with the ICH guidelines and were successfully applied for determination of moxifloxacin, ciprofloxacin, ketorolac and dexamethasone in their laboratory prepared mixtures and pharmaceutical formulations