ZnLaZrSi oxide systems prepared with a silica component of the different nature have been studied in 1,3-butadiene production from aqueous ethanol. The following silica materials were used: KSKG, A-175, A-380, SBA-15, MCM-41, MCM-48, MCF, and dealuminated BEA zeolites. The characteristics of the porous structure of the silica support, such as porosity, pore size distribution, and specific and external surface areas, were found not to be critical parameters for achieving a high 1,3-butadiene yield during the EtOH–H2O mixture conversion in the presence of ZnLaZrSi oxide catalysts. On the contrary, the quantity and strength of Lewis acid sites, which in turn differ depending on the choice of silica material, have a significant impact on 1,3-butadiene selectivity and yield. The highest values of the selectivity of 1,3-butadiene formation (up to 68%) and yield as well as stability toward deactivation in the presence of H2O were achieved over ZnLaZr–KSKG, ZnLaZr–SBA-15, and ZnLa–Zr1SiBEA (with mononuclear isolated tetrahedral Zr(IV) species). The productivity of ZnLa–Zr1SiBEA catalyst accounts for 0.324 g1,3-BD·gcat–1·h–1 (T = 648 K, WHSV = 2.88 h–1, 80 vol % EtOH in water as an EtOH source). The main reason for the decrease in 1,3-butadiene yield in the presence of H2O in the reaction mixture was shown to be a deactivation of acetaldehyde condensation sites on the catalyst surface, while the rate of acetaldehyde formation decreases slightly. According to 1H–13C CP/MAS NMR spectroscopic results, the use of aqueous ethanol as the feed for the ethanol-to-butadiene process is very advantageous to prevent the carburization of the catalysts.