A simple, cost effective, accurate, and precise RP-HPLC method was developed for the simultaneous determination of sulfalene and sulfadoxine in fixed dose dual combinations with pyrimethamine together with their related substances. Proprietary products containing these combinations are often being prescribed in malaria endemic countries. Quantification of the active compounds and impurity profiling was achieved using two standard C18 columns with a mobile phase being composed of 60% (v/v) of a 0.05 M KH2PO4 buffer solution (pH = 2.6) and 40% (v/v) of methanol, applying an isocratic elution mode and a detection wavelength of 215 nm. The method allows a quick quantitative determination of sulfadoxine and sulfalene and the separation of the respective impurities within a total runtime of approximately 15 min and was validated with respect to specificity, linearity, precision, accuracy, limits of detection and quantification, robustness, and stability of the standard and sample solutions. The method is simpler than the corresponding method described in the International Pharmacopoeia and the United States Pharmacopoeia in terms of being easy to apply, being less time consuming, and utilizing reagents and chemicals which are cost efficient.