For the optimal activity of α-amylase from spent brewing grains (SBG) by Aspergillus oryzae NRRL 6270 in solid-state fermentation (SSF), the optimization of three parameters (fermentation temperature, initial substrate moisture and inoculum size) was carried out using the Box-Benhnken response surface methodology (RSM). By analyzing the response surface plots, the optimum range of fermentation temperature, initial substrate moisture and inoculum size for obtaining over 6342.60U/g α-amylase activity were in 29.15～35℃, 68%～71.26% and 2.6×106～1.38×107 spores per gram dry substrate, respectively. By solving the regression equation and also by analyzing the response surface contour plots, the optimal process conditions were determined: under conditions of temperature, 32.96℃; initial substrate moisture, 71.04% and inoculum size, 1.0×107 spores per gram dry substrate, the prediction of α-amylase activity was 6581.63U/g, the above conditions would be 32℃, 71% and 1.0×107 spores per gram dry substrate, respectively. In this situation, the maximum predicted α-amylase activity was 6 445 U/g. The experimental data under various conditions have validated the theoretical values.