Abstract Background A recent combination of aspirin (ASP) and omeprazole (OMP) has been presented in a fixed dosage form for the treatment of many cardiovascular diseases, particularly in patients with gastric diseases. However, ASP is very sensitive to degradation into salicylic acid (SAL) as its main degradation product. Hence, it is very important to develop methods for the determination of ASP and OMP in the presence of SAL. Objective In this study, UV spectrophotometry assisted by different univariate/multivariate post processing algorithms is presented for quantitative determination of ASP, OMP, and SAL without any prior separation. Methods The univariate/multivariate algorithms include double divisor ratio difference and double divisor mean centering as the univariate approaches while the multivariate methods include principal component regression (PCR) and partial least squares (PLS) models. Validation of the univariate methods was done according to International Conference on Harmonization guidelines, while the multivariate models were validated using an external validation set. Results The univariate algorithms displayed excellent regression and validation capabilities in terms of linearity, accuracy, precision, and selectivity. Regarding PCR and PLS, the number of latent variables were carefully optimized, and the model’s validation criteria displayed excellent recoveries and lower errors of prediction. Conclusion Our findings indicate that the developed methods were comparable to the reported chromatographic methods, but are simpler and have much shorter analysis times. Highlights Overall, this report presents the first spectrophotometric methods applied for determination of possible combinations of ASP, OMP, and SAL, and poses these methods as valuable analytical tools for in-process testing and quality control analysis.