Ammonia is regarded as a safe hydrogen energy carrier due to its high hydrogen content and narrow flammable range. Herein, we report a novel metal-organic framework (MOF) templated approach to synthesize highly active catalysts for the hydrogen production from ammonia. Calcination of ruthenium-impregnated UiO-66(Zr)-NH2 leads to formation of small ruthenium nanoparticles (<3 nm) with a strong interaction with the resulting mesoporous zirconia support. These catalysts present a turnover frequency considerably higher than Ru/CNTs catalysts, defying the established believe of 3–5 nm as optimum Ru size for this reaction. Moreover, cesium promoter acts as an electronic modifier of Ru and also as a molecular spacer enhancing the stability under reaction conditions. Despite the exciting potential of this approach, the collapse of MOF framework structures during the calcination process limits the accessibility with an estimated ~16% of the ruthenium accessible, underestimating the actual turnover frequency (TOF) values.