ZrO2-MnO2-ZnO supports were prepared by the co-precipitation method, and then Ni-Na/ZrO2-MnO2-ZnO catalysts were prepared by the impregnation method. In this paper, the reactions to synthesize methyl isopropyl ketone and diethyl ketone by the one-step synthesis method over this catalyst were studied, and meanwhile, the impact of the catalyst preparation conditions and the reaction conditions on catalyst performance was also investigated. It was observed that under the conditions when Ni loading was 25%, calcination temperature was 400 degrees C and reduction temperature was 410 degrees C, this catalyst had good catalytic performance on the reaction. The suitable reaction conditions were achieved: reaction temperature was 400 degrees C; reaction at atmospheric pressure; liquid hourly space velocity of raw material of 0.5 h(-1); and the molar ratio of (methanol)/(methyl ethyl ketone)/(water) was equal to 1/1/1. Under such conditions, the conversion of methyl ethyl ketone could achieve 41.7%, and the overall selectivity of methyl isopropyl ketone and diethyl ketone could achieve 83.3%, which was comparable to the conversion of 38.1% and the selectivity of 82.2% achieved by using palladium as the active material. The good stability made this catalyst have good prospects for industrial application.