The precise control on the combination of multiple metal atoms in the structure of metal-organic frameworks (MOFs) endowed by reticular chemistry, allows the obtaining of materials with compositions that are programmed for achieving enhanced reactivity. The present work illustrates how through the transformation of MOFs with desired arrangements of metal cations, multi-metal spinel oxides with precise compositions can be obtained, and used as catalyst precursor for the reverse water-gas shift reaction. The differences in the spinel initial composition and structure, determined by neutron powder diffraction, influence the overall catalytic activity with changes in the process of in situ formation of active, metal-oxide supported metal nanoparticles, which have been monitored and characterized with in situ X-ray diffraction and photoelectron spectroscopy studies.