Valorization of biomass based on feedstock has become an urgent necessity in terms of sustainability. Materials produced from fossil fuels will eventually run out. Therefore, it is inevitable to evaluate particularly food and agricultural wastes that have no economic value or even threaten the environment. In this study, olive tree (Olea europeae) has been investigated with respect to its by-product such as leaf. Several conventional solvents (ethanol, methanol, acetonitrile, and acetone solutions) were used to obtain an extract rich in total phenolics (TPI), flavonoids (TFI), and antioxidant activity (AA) by means of microwave-assisted extraction (MAE). On the other hand, 3-factor and 3-level central composite design (CCD) was applied via the response surface method (RSM) to determine the optimum experimental conditions of the parameters that were effective on a small number of experiments. Generally, solvent volume was the most effective parameter for each solvent system (P < 0.05). The process parameters of the extraction system were selected as microwave power (150-250 W), time (0.5-1.5 min), and solvent volume (50-100 mL). The best findings for TPI, TFI, and AA were found 10.45-mg GAE/g DL, 9.69-mg CE/g DL, and 96.34% under the optimal conditions (230 W, 1.5 min, and 63.16 mL of 30% acetonitrile solution).