The structural instability of inactivated foot-and-mouth disease virus (FMDV) hinders the development of the vaccine industry. Here, we found that some transition metal ions like Cu2+ and Ni2+ could specifically bind to FMDV capsids at capacities of about 7,089 and 3,448 metal ions per capsid, respectively. These values are about 33- and 16-fold greater than the binding capacity of nontransition metal ion Ca2+ (about 214 per capsid). Further thermodynamic studies indicated that all of these three metal ions bound to the capsids in spontaneous enthalpy-driving manners (Delta G, 0, Delta H, 0, Delta S, 0), and the Cu2+ binding had the highest affinity. The binding of Cu2+ and Ni2+ could enhance both the thermostability and acid-resistant stability of capsids, while the binding of Ca2+ was helpful only to the thermostability of the capsids. Animal experiments showed that the immunization of FMDV bound with Cu2+ induced the highest specific antibody titers in mice. Coincidently, the FMDV bound with Cu2+ exhibited significantly enhanced affinities to integrin beta 6 and heparin sulfate, both of which are important cell surface receptors for FMDV attachment. Finally, the specific interaction between capsids and Cu2+ or Ni2+ was applied to direct purification of FMDV from crude cell culture feedstock by the immobilized metal affinity chromatography. Based on our new findings and structural analysis of the FMDV capsid, a "transition metal ion bridges" mechanism, which describes linkage between adjacent histidine and other amino acids at the interpentameric interface of the capsids by transition metal ion coordination action, was proposed to explain the stabilizing effect imposed on the capsid. IMPORTANCE How to stabilize the inactivated FMDV without affecting virus infectivity and immunogenicity is a big challenge in the vaccine industry. The electrostatic repulsion induced by protonation of a large amount of histidine residues at the interpentameric interface of viral capsids is one of the major mechanisms causing the dissociation of capsids. In the present work, this structural disadvantage inspired us to stabilize the capsids through coordinating transition metal ions with the adjacent histidine residues in the FMDV capsid, instead of removing or substituting them. This approach was proven effective to enhance not only the stability of FMDV but also enhance the specific antibody responses, thus, providing a new guideline for designing an easy-to-use strategy suitable for large-scale production of FMDV vaccine antigen.