(4-Acetamidophenyl) 2-(diethylamino) acetate hydrochloride (propacetamol) is a prodrug of pacetaminophenol (paracetamol). Propacetamol is usually administered intravenously and has a rapid analgesic effect. Moreover, propacetamol is water soluble and is used in postoperative care when the patients cannot take oral or rectal p-acetaminophenol. Studies on propacetamol synthesis on laboratory scale as well as industrial scale with safe, simple and economic procedures are crucial. Over the last few years, a number of studies have been demonstrating the advantages of replacing the traditional heating methods with microwave irradiation. The improved procedure for synthesizing (4-acetamidophenyl) 2-(diethylamino) acetate hydrochloride with N-(4- hydroxyphenyl) acetamide as the starting material is described in this study. Reaction conditions including molar ratio, solvent, catalyst and reaction time were evaluated in order to enhance the synthesis performance. The structure of products obtained after each reaction were determined by using HPLC, MS and NMR methods. The results show a simple process and short reaction time for synthesis of propacetamol from p-acetaminophenol as the starting material. Additionally, the quality and purity of final products meet pharmaceutical standards and high total reaction yield is achieved through the application of microwaves with the suitable catalysts and organic solvents.