Sargassum is a genus of brown macroalgae in the class Phaeophyta, distributed widely in all oceans, including those of Vietnam. Species of this genus have been proven to possess diverse biological activities, such as antioxidant, anti-fungal, and anti-inflammatory, along with many benefits and applications for human health, including anti-diabetic, obesity, and thrombosis. These benefits arise from a diverse chemical composition, with compounds such as fucoidan, mannitol, and especially phlorotannin—a group of phenolic derivatives found predominantly in brown algae. In this study, we evaluated and optimized the factors that affected the extraction process of phlorotannins from Sargassum swartzii (Turn.) C. Ag., a common species of brown macroalgae in Vietnam. The process utilized ethanol and water as the solvent system, and the extraction process was assisted with the use of microwaves. To carry out optimization studies, Response Surface Methodology (RSM) was adopted according to a Central Composite Desisgn (CCD), taking four processing factors into consideration, ethanol concentration (%, v/v), extraction time (minutes), solvent/material ratio (v/w), and microwave output power (W) as independent variables. Phlorotannin concentration (mgPhE/g) and extract mass (mg) were regarded as optimization outcomes. Experimental conditions that produced the highest phlorotannin yield from 10 g of S. swartzii are as follows: Extraction time of 65 minutes, ethanol concentration of 52%, microwave output power of 613 W, and solvent/material ratio of 33/1 (v/w). These conditions corresponded to a phlorotannin concentration of 5.59 ± 0.11 mg PhE/g, and a total extract content of 27.88 ± 0.13 mg/g.