Significance Metal ions have important biological functions and are associated with diseases including cancer and neurodegenerative disorders. The fundamental question of metal ion selectivity in proteins has received continued interest over the past decades. Compared with Na ⁺ /K ⁺ , the selectivity for Mg ²⁺ /Ca ²⁺ is less well understood. Although Mg ²⁺ is a better charge acceptor, calcium-binding proteins with highly charged binding pockets can selectively bind Ca ²⁺ against a much higher concentration of Mg ²⁺ . Here we show that this selectivity is dictated by the many-body polarization effect, which is a cost arising from the dense packing of multiple residues around the metal ion. By combining geometric constraint and the many-body effect, it is possible to fine-tune the selectivity for metal ions of different sizes.