The association of Ca2+ and Cu2+ to serine was investigated by means of B3LYP DFT calculations. The [serine–M]2+ (M = Ca, Cu) potential energy surfaces include, as does the neutral serine, a large number of conformers, in which a drastic reorganization of the electron density of the serine moiety is observed. This leads to significant changes in the number and strength of the intramolecular hydrogen bonds existing in the neutral serine tautomers. In some cases, a proton is transferred from the carboxylic OH group to the amino group and accordingly, some of the more stable [serine–M]2+ complexes can be viewed as the result of the interaction of the zwiterionic form of serine with the doubly charged metal ion. Whereas the interaction between Ca2+ and serine is essentially electrostatic, that between Cu2+ and serine has a non-negligible covalent character, reflected in larger electron densities at the bond critical points between the metal and the base, in the negative values of the electron density between the two interacting systems, and in much larger Cu2+ than Ca2+ binding energies. More importantly, the interaction with Cu2+ is followed by a partial oxidation of the base, which is not observed when the metal ion is Ca2+. The main consequence is that in Cu2+ complexes a significant acidity enhancement of the serine moiety takes place, which strongly favors the deprotonation of the [serine–Cu]2+ complexes. This is not the case for Ca2+ complexes. Thus, [serine–Ca]2+ complexes, like those formed by urea, thiourea, selenourea, or glycine, should be detected in the gas phase. Conversely, the complexes with Cu2+ should deprotonate spontaneously and therefore only [(serine–H)–Cu]+ monocations should be experimentally accessible.