The one-pot liquid-phase synthesis of methyl isobutyl ketone (MIBK) from acetone and H-2 is a significant process in the fine-chemicals industry. In this paper, we fabricated a series of TiO2 SiO2/SiO2(F)&Pd/Cor bifunctional catalysts and optimized the ratio of TiO2 to SiO2 to be 1. The catalyst with the optimal mole ratio of TiO2 to SiO2 was further investigated in a long-term operation in a trickle bed reactor, which delivered a stable MIBK selectivity of 8393% at 26-36% acetone conversion for 300 h. The characterizations of Fourier transform infrared spectra, Raman spectra, thermogravimetric analysis, X-ray diffraction, X-ray photoelectron spectroscopy, temperature-programmed desorption of CO2 and NH3, and pyrolysis infrared spectra reveal that the active sites of acetone condensation and dehydrogenation could be attributed to the Ti-O-Si bonds. Deactivation of the catalyst resulted from a decrease of the active sites because of the aggregation of TiO2 and carbonaceous accumulation on the catalyst surface.