Abstract: The selective interaction between reagent molecules and mineral surface ions is the basis of flotation separation. The metal ion in mineral surface is far different from the free ion. The former, influenced by surrounding coordination and steric hindrance among other factors, is in a semi-constrained state. From the perspective of coordination chemistry, this paper illustrates the interaction of reagent molecules with surface ions, that is, secondary coordination of reagent molecules with metal ions that have been coordinated with surrounding atoms on mineral surface. Secondary coordination features steric hindrance and ligand field effects. For oxide ores that coordinate with weak-field ligands and sulfide ores that coordinate with strong-field ligands, coordinate bonding and π-backbonding play a dominant role in the interaction between collectors and metal ions, respectively. Sulfhydryl collectors including xanthate are prone to interact with low-spin metal ions while oxydryl collectors such as oleic acid are prone to interact with metal ions with strong electrostatic properties. Depressants containing π orbitals like NaCN, Ca(OH)+ and sulfites tend to interact with pyrite bearing a number of π electron pairs and barely interact with galena containing no π electron pair. Crystal field stabilization energy influences the stability of reagent adsorption on mineral surface. The effects of flotation critical pH and reagent addition order on depression are also relevant to crystal field stabilization energy. For the first time, coordination chemistry of flotation introduces classical concepts and theories in modern chemistry, including orbital structures, electron spin and symmetry matching into mineral flotation, which serves as a unified theoretical description of both mineral crystal structures and flotation reagent properties and reveals the essence of reagent-mineral interaction at an electron-orbital level. This paper has significant theoretical and practical implications for targeted design for reagent molecules and development of novel reagents.