A zinc and tantalum-containing mesoporous silica catalyst highly active and selective in the Lebedev process has been prepared using the one-pot TUD-1 methodology. Selectivity towards butadiene reached 60–70%, making Zn–Ta-TUD-1 one of the best performing catalysts in the literature. To rationalize these results and establish a structure–activity relationship, a series of similar catalysts was prepared and characterized. Nitrogen physisorption, XPS, ICP-AES, XRD, TEM, UV-vis spectroscopy, TGA NH3-TPD, H2-TPR and FT-IR techniques were used. The most active samples were found to possess a large specific surface area and highly dispersed metal oxide phase incorporated within the mesoporous silica matrix. In combination with catalytic testing, characterization also showed a direct correlation between the number of Lewis acid sites and butadiene yield, confirming the structure–activity relationship theory prevalent for the Lebedev process. Deactivation of Zn–Ta-TUD-1 was also studied using the same techniques to characterize the properties of spent catalysts. It was found that the accumulation of heavy carbonaceous species caused a reduction of specific surface area and pore size coinciding with the observed loss in activity. Nevertheless, the pores of TUD-1 were large enough to avoid total pore blockage and a high selectivity could be maintained for 72 hours.