Herein, we prepared a V/SBA-16 catalyst using vanadyl acetylacetonate as a precursor and SBA-16 nanoporous silica as a support via an immobilization technique. The ordered mesoporous structure of catalyst was determined by X-ray diffraction  and transmission electron microscopy techniques , and the catalyst was evaluated in the benzene hydroxylation to phenol with hydrogen peroxide (H2O2) as a green oxidant. The effects of three key factors, namely reaction temperature (°C), H2O2 content (mL) and catalyst amount (g) at five levels (“1.68, “1, 0, +1, +1.68), and also their interaction on the phenol yield were investigated using response surface methodology combined with central composite design. The high correlation coefficient (R2), i.e., 0.983, showed that the data predicted using RSM were in good agreement with the experimental results. The optimization results also exhibited that high phenol yield (17.09%) was achieved at the optimized values of the operating variables: the reaction temperature of 61 °C, H2O2 content of 1.69 mL and a catalyst amount of 0.1 g. In addition, response surface methodology provides a reliable method for optimizing process variables for benzene hydroxylation to phenol, with the minimum number of experiments.