Two types of copper-based dehydrogenation nanocatalysts (Cu/ZnO/Al2O3 and Cu/SiO2) were prepared from various precursors by impregnation (IM), sol-gel (SG) and co precipitation (COPRE) methods. The structures of samples were characterized by N2 adsorption-desorption, XRD, XRF, TPR, N2O-Titration, FT-IR, FE-SEM and TEM techniques. The catalytic performance tests in vapor-phase dehydrogenation of 2-butanol to methyl ethyl ketone (MEK) were carried out in a fixed-bed reactor at a temperature of 260 oC under atmospheric pressure and LHSV of 4mL/(h·g cat). The experimental results indicated that (i) the copper oxide over the COPRE nanocatalyst was reduced at a lower temperature (222 oC) in comparison with the CuO reduced on the SG and IM samples (243 and 327 oC, respectively). Also, the percentage of reduction of CuO species on COPRE catalyst was the highest (98.8%) in comparison with the two other samples, (ii) the COPRE nanocatalyst exhibited the highest activity for the dehydrogenation of 2-butanol to MEK, and (iii) co-precipitation method was selected as an optimum method for preparation of nanocatalyst. The central composite experimental design method was applied for investigation of the effects of four critical preparation factors on the MEK selectivity of Cu/ZnO/Al2O3 nanocatalyst. The results showed that Cu/Zn molar ratio and precipitation pH are the most effective factors on the response and the optimum conditions for synthesis of Cu/ZnO/Al2O3 nanocatalyst with maximum selectivity of MEK were T(pre)=67.5 oC, T(aging)=68.8 oC, pH(pre)=7.27 and Cu/Zn molar ratio=1.38. The performance of the prepared nanocatalyst at the optimum conditions was comparable to the commercially available nanocatalyst.