Objectives: The main aim of this study is to apply smart, simple, rapid and accurate methods for simultaneous determination of Paracetamol (PAR), Chlorzoxazone (CXZ) and Diclofenac potassium (DIC), in their bulk powder and tablet dosage form. Methods: Potent processing methods were used which were based on the application of continuous wavelet transform (CWT) and Savitsky–Golay derivatization (SAVGOL) as univariate spectrophotometric methods, partial least squares (PLS) and synergy interval partial least squares (siPLS) as multivariate methods. Results: PAR, CXZ and DIC were determined in the concentration ranges of 2–30, 2–50 and 2–30 μg/mL, respectively. The regressing and validation parameters of the proposed methods revealed the efficiency of the methods.  The results obtained for the analysis of those drugs by the proposed methods were statistically compared to those obtained by applying a reported high performance liquid chromatographic method. Statistical comparison was done, and no significant difference was found between the proposed methods and the reported one. Conclusion: Successful determination of ternary mixture containing PAR, CXZ and DIC was achieved with no need for tedious sample separation or pre-treatment derivatization which is considered a great benefit in quality control laboratories.