The selective hydrolysis of proteins by non‐enzymatic catalysis is difficult to achieve, yet it is crucial for applications in biotechnology and proteomics. Herein, we report that discrete hafnium metal‐oxo cluster [Hf₁₈O₁₀(OH)₂₆(SO₄)₁₃⋅(H₂O)₃₃] (Hf₁₈), which is centred by the same hexamer motif found in many MOFs, acts as a heterogeneous catalyst for the efficient hydrolysis of horse heart myoglobin (HHM) in low buffer concentrations. Among 154 amino acids present in the sequence of HHM, strictly selective cleavage at only 6 solvent accessible aspartate residues was observed. Mechanistic experiments suggest that the hydrolytic activity is likely derived from the actuation of Hf^IV Lewis acidic sites and the Brønsted acidic surface of Hf₁₈. X‐ray scattering and ESI‐MS revealed that Hf₁₈ is completely insoluble in these conditions, confirming the HHM hydrolysis is caused by a heterogeneous reaction of the solid Hf₁₈cluster, and not from smaller, soluble Hf species that could leach into solution.