In this study, we measured total flavonoids after extracting the total flavonoids from lemongrass which is known to have a high content of antioxidant ingredients when using microwave energy. Also, optimal extraction conditions of active ingredients using central composite design-response surface methodology (CCD-RSM) were presented. Both ultrapure water and alcohol were used as extraction solvents and the volume ratio of ethanol/ultrapure water, microwave irradiation time, and microwave irradiation power were set as independence variables. And the extraction yield and total flavonoids were measured. The optimal extraction conditions using CCD-RSM were the volume ratio of ethanol/ultrapure water = 56.3 vol.%, the microwave irradiation time = 6.1 min, and the microwave irradiation power = 574.6 W. We could also obtain expected results of yield = 17.2 wt.% and total flavonoids = 44.7 μg QE/mL dw under the optimum conditions. The comprehensive satisfaction degree of this formula was 0.8562. The P-value was calculated for the yield of 0.037 and the total flavonoids content of 0.002. The average error from actual experiments established for the verification of conclusions was lower than 2.5%. Therefore, a high favorable level could be obtained when the CCD-RSM was applied to the optimization of extraction process.