The polyphenol extract from olive stone was optimized by the simultaneous maximization of the yield in total phenolic content (TPC), total flavonoids content (TFC), 2,2-diphenyl-1-picrylhydrazyl free radical-scavenging activity (DPPH), ferric reducing/antioxidant power (FRAP), and three individual polyphenols (hydroxytyrosol, syringic acid, and oleuropein) using response surface methodology (RSM). Extraction temperature (40, 50, and 60 degrees C), extraction time (30, 60, and 90min), and solvent type (methanol, ethanol, and acetone) were identified as the main variables influencing the extraction efficiency. Face-centered central composite design (FCCD), which consists of 39 factorial experiments including 5 replicates at the central point, generated satisfactory models for the optimization of independent variables. The results showed that the extraction temperature, extraction time, and solvent type had significant effects on all responses except DPPH and FRAP. The optimum conditions for extraction temperature, extraction time, and solvent type were determined as 40 degrees C, 89.49min, and methanol, respectively. These values verified with confirmation experiments, and thus, the suitability of the developed models was proven. This methodology could be preferred to ensure that polyphenol extracts were obtained efficiently from the by-products, such as the olive stone in the food industry.