A simple, rapid, sensitive, robust, RP-HPLC and UV/Vis-Spectrophotometric scheme including AUC (UV-AUC) analytical protocol was developed and validated for the analysis of Docosanol in loose and in cream formulation. Development of RP-HPLC method was achieved on a LC- Hypersil BDS C18 column (100 mm x 4.6 mm; 3 μl) by gradient mode at ambient temperature, employing a mobile phase methanol and (0.01%, v/v) ammonia in ratio of (70:30, v/v), keeping pH at 7.5 at a flow rate of 0.8 mL/min and recognition at 243 nm. UV-AUC method was customized with an aid of a double beam UV- Spectrophotometer (UV-2450, Shimadzu), employing chloroform as a solvent. Area Under Curve (AUC) is measured in the wavelength ranges between 240-245 nm taking maximum absorbance (λ max) at 243 nm. The drug Docosanol is chemically modified into a chromophoric derivative prior to development of analytical methods by applying principles of green chemistry. The reaction is performed under microwave so as to reduce reaction time and to improve yield of the product. The method succeeded over the validation parameters.