Lomefloxacin ethyl ester was prepared from 2,3,4-trifluoroaniline in ionic liquid in a one-pot procedure by condensation with EMME (ethoxymethylenemalonic diethyl ester), cyclization, ethylation, and condensation with 2-methyl piperazine. After its hydrolysis and salifying with hydrochloric acid, lomefloxacin hydrochloride was obtained with an overall yield of 58.4%. Compared with current lomefloxacin hydrochloride synthesis technology, this approach simplified its synthesis procedures, shortened its synthesis time, and eliminated the usage of volatile organic solvents.