The nature of interactions between the neutral/protonated mitoxantrone and the cucurbit[n]uril (n = 7, 8) host system was analyzed by employing density functional theory calculations. A comparison between the inclusion complexes of CB[7] and CB[8] shows various subtle differences in the complexation thermodynamics, given as changes in the Gibbs energy. Doubly and quadruply charged mitoxantrone (MX) molecules spontaneously form complexes in a water solvent, which are modeled using the polarizable continuum model approach. Both CB[7] and CB[8] complexes are stable as the geometry of the cavity allows for electrostatic interactions between the charged MX arms and the rim of the CB cavity. CB[8] also forms a stable complex with two mitoxantrone molecules with their aromatic rings stacked inside the cavity. Both CB[7] and CB[8] show properties that can be utilized in drug delivery.