In the present study, design of experiments (Orthogonal experiment) was used to find an optimal combination for the factors, which affect the catalytic activity of nano-crystalline TiO2 powder synthesized by sol–gel method. Sixteen kinds of TiO2 powder were prepared by changing three material ratio at four levels. The effects of calcinations temperature on the catalyst activity of TiO2 were investigated by single factor experiments. TiO2 were characterized by XRD. The results of design of experiments are examined by the direct observation analysis. The preparation conditions have been optimized as material ratio nTi(OC4H9)4: nH2O: nHN(C2H5OH)2: nC2H5OH=1:2:2.5:20, mean 16.8 nm TiO2 nanoparticle with anatase structure obtained at 500°C calcination. The photodegradation efficiency of methylene blue in aqueous solution is 99 % under 1g/L catalyst.