The Preyssler anion, of general formula [Xn+P5W30O110](15-n)-, is the smallest polyoxometalate (POM) with an internal cavity allowing cation exchange with the solution. The Preyssler anion features a rich chemistry evidenced by its ability to accept electrons at low potentials, to selectively capture various metal cations, and to undergo acid-base reactions. A deep understanding of these topics is herein provided by means of DFT calculations on the title series of compounds. We evaluate the energetics of the release/encapsulation process for several Xn+ cations and identify the effect of the encapsulated ion on the properties of the Preyssler anion. We revisit the relationship between the internal cation charge and the electrochemical behavior of the POM. A linear dependence between the first one-electron reduction energies and the encapsulated Xn+ charge is found, with a slope of 48 mV per unit charge. The protonation also shifts the reduction potential to more positive values, but the effect is much larger. In connection to this, the last proton’s pKa = 2 for the Na+ derivative was estimated to be in reasonable agreement with experiment. The electronic structure of lanthanide derivatives is more complex than conventional POM structures. The reduction energy for the CeIV-Preyssler + 1e– —> CeIII-Preyssler process was computed to be more exothermic than that of very oxidant species such as S2Mo18O624-.