Metal promotion in heterogeneous catalysis requires nanoscale-precision architectures to attain maximized and durable benefits. Herein, we unravel the complex interplay between nanostructure and product selectivity of nickel-promoted In O in CO hydrogenation to methanol through in-depth characterization, theoretical simulations, and kinetic analyses. Up to 10 wt.% nickel, InNi patches are formed on the oxide surface, which cannot activate CO but boost methanol production supplying neutral hydrogen species. Since protons and hydrides generated on In O drive methanol synthesis rather than the reverse water-gas shift but radicals foster both reactions, nickel-lean catalysts featuring nanometric alloy layers provide a favorable balance between charged and neutral hydrogen species. For nickel contents >10 wt.%, extended InNi structures favor CO production and metallic nickel additionally present produces some methane. This study marks a step ahead towards green methanol synthesis and uncovers chemistry aspects of nickel that shall spark inspiration for other catalytic applications.