Aspirin and omeprazole combining has proven their effectiveness clinically in the treatment and prevention of cardiovascular diseases in patient with gastric diseases and gastric ulcers. Simultaneous determination of omeprazole and aspirin in their combination is a challenge due to the overlapping spectra of these drugs. Six smart and different spectrophotometric methods were developed for the analysis of omeprazole and aspirin in binary mixture and pharmaceutical dosage form. These smart methods characterized by simplicity and accuracy. The first two methods based on minimal mathematical data processing based on the zero order absorption spectra were; dual wavelength and advanced absorbance subtraction methods. The third method is first and second derivative spectrophotometric method that based on derivative spectra. The last three methods based on ratio spectra manipulation are named; ratio difference, mean centering and derivative ratio spectrophotometric methods. The linearity range of omeprazole was 2–20 μg/mL for dual wavelength method and 2–30 μg/mL for the other ones, while aspirin showed a good linearity over a range of 2.5–30 μg/mL for all methods. The correlation coefficients were greater than 0.999. The results of the developed methods are statistically compared with each other and with the results of the reported HPLC method showing no significant difference. The greenness of the developed methods was assessed using eco-scale scoring method revealing excellent greenness of the applied methods. This spectrophotometric methods is more sensitive and greener with comparing by the reported one so, these developed methods are considered eco-friendly to the environment.