A reversed‐phase high‐performance liquid chromatography with diode array detection method was developed with the aid of statistical approaches for the determination of acemetacin and its official impurities 4‐chlorobenzoic acid and indometacin. Two‐level full factorial design was used to optimize the used mobile phase where three chromatographic variables were studied, amount of acetonitrile, amount of H3PO4 acid, and mobile phase flow rate. The selected responses were analysis time and chromatographic resolution between adjacent peaks (peaks of indometacin and acemetacin). The impacts of the amount of acetonitrile and the mobile phase flow rate individually were significant on the analysis time (P = 0.0277 and 0.0424, respectively). Also the amount of acetonitrile had a meaningful effect on the resolution (P = 0.0085). Finally, chromatographic separation was performed on Zorbax® Eclipse C18 column using acetonitrile/water (containing 0.05% H3PO4; 55:45, v/v) at 1.5 mL/min as an optimized mobile phase using full factorial experimental design with UV detection at 230 nm. 4‐Chlorobenzoic acid appeared at 3.29 min, indometacin at 9.07 min and acemetacin at 10 min. The method fulfilled United States Pharmacopoeia validation standards. In addition, system suitability parameters were calculated, and the results were within acceptable criteria. Commercially available tablets were analyzed, and good recoveries were obtained. Statistical comparison of the method with the reported one showed no significant difference.