Dеtеrmination of nonsteroidal anti-inflammatory drugs (NSAIDs) in pharmacеutical formulations hеlps to еnsurе that thеy arе manufacturеd to thе corrеct spеcifications. Consequently, simple, reliable, and environmentally friendly analytical methods are needed for the quality control of NSAID formulations. In this study, a novel and green liquid chromatographic method was developed for the determination of nimesulide (NIM) and naproxen (NAP) in gel formulations by employing ethanol as a green alternative to hazardous methanol and acetonitrile. The high viscosity of ethanol was compensated by employing a Chromolith HighResolution RP18e monolithic column (100 × 4.6 mm) with low flow resistance. Box-Behnken design with desirability function was employed for the optimization of selected significant parameters: pH (2.8-4), ethanol ratio in the mobile phase (35-55%), and flow rate (0.7-1.5 mL/min). Under optimum conditions, satisfactory separation of analytes was achieved within 5 min. Calibration curves for both analytes were linear between 1-50 μg/mL. Accuracies of intra- and inter-day experiments at low-, middle-, and high-quality control levels ranged from 99.0-101.5% with relative standard deviation values lower than 2.3%. The limits of detection were 0.27 and 0.62 µg/mL for NIM and NAP, respectively. The applicability of the method was demonstrated by analyzing gel formulations. The results of this study indicated that monolithic columns in combination with ethanol as a mobile phase component could be considered a desirable and green alternative for the routine analysis of NSAIDs in quality control laboratories.