The effect of initial microstructure and morphology of the NiO precursor on morphological peculiarities and catalytic properties of the multiphase catalysts for the CO hydrogenation was studied using in situ X-ray powder diffraction and transmission electron microscopy. Under the CO hydrogenation conditions, the NiO sample with the most developed (100) plane was found to be transformed into the Ni/Ni3C/NiO catalyst, giving CH4 as a major product of the reaction. The NiO sample with the most developed (111) plane was transformed into the catalyst containing Ni3C/NiO and producing equal amounts of CH4 and CO2. The catalytic properties of the samples were shown to be interrelated to both the composition of the multiphase catalyst and the morphology of each of the component. A step-by-step comparison between variations in the phase composition and the catalytic activity of the samples during a long-term treatment under the reaction conditions was carried out.