Background: Sesamum indicum is a widely cultivated crop with edible seeds which are well known for its rich antioxidant properties. The plant leaves have also been reported to have health functional attributes such as lowering cholesterol level in body, reducing cancer, and acting as antihypertensive resource. Objective: The aim of the study was to optimize the effects of solvent-based microwave-assisted extractions (SMAEs) of phenolic compounds from S. indicum (Sesame) leaves using combined approach of response surface methodology and particle swarm optimization (PSO). Materials and Methods: SMAEs along with response surface model development and its optimization by PSO were done. The optimization parameters such as microwave power (180–900 W), extraction time (1–30 min), solid-liquid ratio (1:10–40 g/mL), and solvent (methanol) concentration (50–70%) were employed to obtain extracts showing higher total phenolic content (TPC) and antioxidant activities by 2,2-diphenyl-1-picrylhydrazyl (DPPH) value. Results: The maximum TPC and DPPH values were 206.14 ± 2.70 mg GAE/100 g and 96.04 ± 1.67% for extracts against 51.38% methanol concentration, 1:23 g/mL solid-liquid ratio, 900 W power level, and 16.95 min of extraction time, respectively. The gas chromatography–mass spectrometry chromatographs showed the presence of various essential phytocomponents such as ascorbic acid, phytol, and flavonol as functional molecules at 26.79, 29.03, and 39.70 min retention time, respectively. The high-performance liquid chromatogram further confirmed the presence of quercetin, chlorogenic acid, and gallic acid at a concentration of 11.25, 4.28, and 1.61 ppm, respectively. Conclusion: The results of this study suggest application of PSO algorithms as an efficient approach to optimize the extraction of bioactive components from Sesame leaves which can be used as a potential source for functional and nutraceutical food development.