Smart spectrophotometric methods were introduced for the simultaneous determination of Norfloxacin (NF) and Tinidazole (TZ) in pure forms and their tablet pharmaceutical formulation. The proposed methods under study are. Ratio Difference (RD) in which the amplitude difference at 273 and 306 nm for the determination of NF and TZ was measured. Mean Centering of Ratio spectra (MCR) in which the peak amplitude at 270 nm for the determination of NF and summation of the peak amplitudes at 270 and 304 nm for the estimation of TZ were measured. Dual Wavelength (DWL) in this method, wavelengths 210 and 287 nm were used for NF determination, 270 and 287 nm for TZ determination. Bivariate method (BIV) in which two wavelengths 280 and 305 nm for quantitative estimation of NF and TZ were used. All of the previous methods determined successfully NF and TZ in concentration ranges of 1-12 μg/ml and 3-30 μg/ml, respectively. Chemo metric assisted method Partial Least-Squares (PLS). All of the developed methods were validated using International Conference on Hormonization (ICH) guidelines and statistically compared to High Performance Liquid Chromatography (HPLC) reported method. The adopted methods can be applied for the regular analysis of NF and TZ mixture in QC laboratories.