Eleutherine bulbosa bulbs, an endemic plant in Indonesia, have enormous potential as raw materials for pharmaceutical products. Therefore, it is necessary to strengthen and develop extraction methods that are easy, rapid, and efficient to enrich targeted secondary metabolites. This study aims to optimize the microwave-assisted extraction (MAE) method conditions for polyphenol metabolite from E. bulbosa bulbs. The MAE method (with different conditions) was applied to extract total polyphenol content (TPC) from E. bulbosa bulbs. TPC values were determined using a 96-well microplate reader spectrophotometry method and Folin–Ciocalteu reagent. The variables of MAE, as an experimental design-independent variable, were involved. The MAE method condition was optimized using response surface methodology (RSM) and Box–Behnken design based on the TPC value. The MAE condition was optimized with 60% ethanol, sample–solvent ratio of 1:10 g/mL, and 50% Watts of microwave power for 10 min. The quadratic regression analysis was achieved to predict the TPC value using the equation: TPC value = 28.63–5.545A +2.211B –0.741C +1.995D – 4.045AB +0.856AC –7.541BC +1.961CD –8.342A2–0.071B2 +1.840C2–1.535D2. For the scale-up confirmation test, a 50-g sample was used to prove the validity of the equation to predict the TPC value, yielding 35.33 ± 2.13 mg gallic acid equivalent/g samples. The optimum of the MAE condition recommended based on the results of RSM analysis can be applied directly to the enrichment of polyphenols metabolite constituent of E. bulbosa easily, cheaply, quickly, and efficiently.