Four simple, precise, accurate and validated spectrophotometric methods have been developed for the simultaneous determination of ofloxacin (OFL) and bromfenac sodium (BROM). Firstly, first and second derivative spectrophotometric methods (1D &2D) using a zero-crossing technique utilizing 309.3 and 257.5 nm for OFL and 290.7 and 246.5 nm for BROM as optimum working wavelengths in a binary mixture, respectively. Secondly, the first derivative ratio spectrophotometric method (1DD) in which peak amplitudes at 297.3 nm and 260.7 nm were chosen to simultaneously estimate OFL and BROM, respectively. Thirdly, dual wavelength (DW) method based on two selected wavelengths for each drug in such a way that the difference in absorbance is zero for the second one. At wavelengths 296.4, 348.4 nm BROM has equal absorbance values, therefore, these two wavelengths have been used to determine OFL. Similarly, 271.7 nm and 313.1 nm were selected to determine BROM in the combined formulation. Finally, the fourth method depends on ratio difference spectrophotometry (RDSM), in which the difference between amplitudes at 305.6 nm and 326.5 nm on the ratio spectrum of the mixture was directly proportional to the concentration of OFL; independent of the interfering components. Similarly, the difference between amplitudes at 265.1 nm and 275.4 nm on the ratio spectrum was used for the determination of BROM.The linearity was confirmed in the range of 4 – 18 µg/ml for OFL and BROM for the four methods. The proposed methods were used to determine both drugs in their laboratory prepared mixture and combined formulation with mean percentage recoveries of 99.41 ± 1.35% for OFL and 99.98 ± 1.30 % for BROM in method (A). In method (B), the mean percentage recoveries were 101.70 ± 1.61% for OFL and 101.90 ± 1.45% for BROM. In method (C) OFL was 99.57 ± 1.61% and 100.90 ± 1.62% for BROM. Finally, in method (D) the mean percentage recoveries were 99.37 ± 1.67% for OFL and 100.70 ± 1.59% for BROM.The developed methods were successfully employed for determination of OFL and BROM in laboratory prepared mixtures and combined formulation showing satisfactory recoveries. Methods validation was performed according to the International Conference on Harmonization (ICH) guidelines. The obtained results conformed to the accepted ranges of recovery, precision and repeatability.