Maximizing the yield of bioactive molecules extracted from plant materials requires the investigation of extraction process variables; therefore, in this research, a traditional aqueous solid–liquid extraction method was employed on two distinct grape pomace skin samples. The grape skin pomace represents a potentially valuable source of biologically active compounds, particularly polyphenols. Experiment 1 utilized ground grape pomace skin, whereas experiment 2 utilized grape pomace skin that had been both dried and ground beforehand. Employing a Box–Benkhen experimental design and response surface modeling in the Statistica 14.0 software package, this study evaluated the impact of temperature, extraction time, solid-to-liquid ratio (S/L), and mixing speed on extraction efficiency. The extracted compounds were assessed for both physical properties (conductivity, total dissolved solids, and pH) and chemical properties (total polyphenol content and antioxidant activity using 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays). The optimization matrix design identified the specific conditions required to achieve the optimal physical and chemical properties of grape skin extract as follows: (i) for experiment 1, extraction time (t) = 15 min, temperature (T) = 80 °C, solid-to-liquid ratio (S/L) = 10 g/L, and mixing speed (rpm) = 500 1/min and (ii) for experiment 2, extraction time (t) = 15 min, temperature (T) = 80 °C, solid-to-liquid ratio (S/L) = 10 g/L, and mixing speed (rpm) = 375 1/min. Under optimal process conditions, 26.1284 mgGAE/gd.m. and 25.1024 mgGAE/gd.m., respectively, were obtained. These findings demonstrate the effectiveness of the optimization process in identifying precise extraction conditions that yield the optimal chemical properties of grape skin extracts.