According to the relevant regulation of ICH Q11 on the development and manufacture of drug substances, the advantages and shortcomings of reported synthetic methods of Naphazoline Hydrochloride and the possible origination of it’s impurities specified in the European Pharmacopoeia were analyzed, and then the modified synthesis route was designed to control the generation of impurities based on the concept of Quality by Design. Using 1-naphthylacetic acid as the starting material, the target compound was obtained through amidation reaction, amide dehydration reaction, catalytic addition-cyclization reaction and salt formation reaction. The results show as follows: In the amidation reaction, using dichloromethane as the solvent, n (1-naphthylacetic acid): n (di-tert-butyl dicarbonate)﹕n (ammonia) = 1﹕1.2﹕1.2, the yield is 88.6％; In the dehydration reaction and the addition-cyclization reaction, N, N-dimethylformamide is used as the solvent, the workup procedure is simple and the intermediate purity is high; In the salt formation reaction, n (Naphazoline free base)﹕n (36％ Hydrochloric acid) = 1﹕1.48, the yield is 90.1％. After optimizing the process parameters, the total yield is 50.83％ with four successive steps, and the four impurities listed in the European Pharmacopoeia are not detected. The synthesis process has advantage of mild reaction conditions, which is suitable for industrial application.