The effect of the protein environment on the formation and stabilization of an elusive catalytically active polyoxometalate (POM) species, K6[Hf(α2‐P2W17O61)] (1), is reported. In the co‐crystal of hen egg‐white lysozyme (HEWL) with 1, the catalytically active monomeric species is observed, originating from the dimeric 1:2 POM form, while it is intrinsically unstable under physiological pH conditions. The protein‐assisted dissociation of the dimeric POM was rationalized by means of DFT calculations. The dissociation process is unfavorable in bulk water, but becomes favorable in the protein–POM complex due to the low dielectric response at the protein surface. The crystal structure shows that the monomeric form is stabilized by electrostatic and water‐mediated hydrogen bonding interactions with the protein. It interacts at three distinct sites, close to the aspartate‐containing hydrolysis sites, demonstrating high selectivity towards peptide bonds containing this residue.