Copper and zirconium oxide clusters were highly dispersed on mesocellular siliceous foam (MCF), a mesoporous silica support with ultra large, interconnected nanopores. These catalysts (denoted as Cu/MCF and Zr/MCF) were separately loaded into two fixed bed reactors as catalysts for the conversion of ethanol (EtOH) to 1,3-butadiene (BD). Under optimal conditions, high BD selectivity (up to 73%) and ethanol conversion (up to 96%) were achieved at weight hourly space velocities of 1.5 and 3.7 h–1. This translates to an unprecedented productivity of 1.4 gBD/gcatalyst h–1 (208 gBD/lcatalyst h–1). The high catalytic performance is attributed to the highly selective and active catalysts. The EtOH dehydrogenation activity of Cu/MCF could be accurately controlled in the first reactor, which delivers a fixed ratio of the acetaldehyde/EtOH mixture to Zr/MCF in the second reactor. The optimal ratio minimizes EtOH dehydration to ethylene by Zr/MCF, while maximizing the selectivity to BD. MCF was found to be superior over commercial porous silica in terms of EtOH conversion, BD selectivity, and tolerance to coking. High BD selectivity was maintained with a slight decrease in EtOH conversion over 42 h, which was readily restored upon regeneration by thermal treatment in air.