The main goal of the research was to optimize microwave-assisted simultaneous distillation and extraction (MA-SDE) using response surface methodology (RSM), based on Box−Behnken design (BBD). A process was designed to extract the essential oil from the leaf sheath of Siam cardamom. The experimental data were fitted to quadratic equations, and the experiment conditions for optimal extraction of 1,8-cineole were extraction time 87.68 min, material-to-water ratio 1:13.18 g/mL and microwave power 217.77 W. Under such conditions, the content of 1,8-cineole was 157.23 ± 4.23 µg/g, which matched with the predicted value. GC−MS results indicated the presence of predominant oxygenated monoterpenes including 1,8-cineole (20.63%), iso-carveol (14.30%), cis-p-mentha-1(7),8-dien-2-ol (12.27%) and trans-p-2,8-menthadien-1-ol (9.66%), and oxygenated contents were slightly higher in the MA-SDE and extraction compared to usual SDE. In addition, the essential oil extracted by MA-SDE exhibited strong antibacterial effects against the tested Gram-positive bacteria. Scanning electron micrographs provided more evidence of destruction of the leaf sheath treated by MA-SDE. Conclusively, microwave-assisted simultaneous distillation and solvent extraction appear to be an effective technique for the separation of essential oils enriched 1,8-cineole from Siam cardamom leaf sheath in a shorter time.