The olive tree historically provided economic benefits to the countries in Mediterranean basin as a source of products contributing to health promotion. Some of the health benefits attributed to olive tree leaves are related to phenolic composition. In this study, a 10-point augmented simplex-centroid design was used to formulate a three-component mixture system using water, ethanol and methanol, adequate for the extraction of phenolics from olive leaves. Phenolic and flavonoid content, antioxidant activity with 2, 2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid), oleuropein, and luteolin7- O-glucoside concentrations were selected as responses. The optimal extraction mixture was: 12.7% water, 14.8% ethanol, and 72.5% methanol. The yields of total phenolic and flavonoid compounds, oleuropein, and luteolin-7-O-glucoside were 163.69 ± 6.35 mg gallic acid g−1, 114.69 ± 3.56 mg rutin g−1, 858.29 µg g−1, and 21.04 µg g−1 dry weight of olive leaves. The antioxidant capacity was 238.71 ± 4.35 mM equivalent Trolox per g−1 dry weight of olive leaves.