A set of experimental designs was executed to attain the optimal reaction parameters of chemical derivatization of midodrine hydrochloride (MD·HCl) in oral formulas via a Hantzsch condensation reaction. The process variables, such as reaction temperature, heating time, reagent volume, and pH were screened by operating a 2-level full factorial design. Variables proved to be significant (p < 0.05) were warily attuned utilizing a response surface methodology (RSM) with a face-centered central composite design. The suggested model represented a perfect example for probing the efficiency of factorial designs in optimizing the reaction conditions and maximizing the output. In this itinerary, the developed model allowed the evaluation of main, interaction and quadratic effects of tested variables. A linear calibration curve was obtained in the range of 2.00–18.00 μg mL⁻¹ with a high value for the coefficient of determination (R² = 0.9999). Statistical validation of the proposed technique was done using ANOVA in two successive steps. Moreover, a D-optimality design was employed to minimalize the variation in the regression coefficients of the fitted model. The optimized technique was used to determine MD·HCl in tablets and oral drops using a simple extraction procedure prior to measuring the absorbance at 330 nm. The results obtained were in good agreement with the label claim with no interference from adjuvants commonly co-formulated with the drug. Inter- and intra-day precision, limits of detection and quantification, and relative standard deviation have been assessed following ICH guidelines for evaluation of analytical procedures, and the results obtained were satisfactory.