Achieving an efficient separation of chemically similar Am3+/Eu3+ pair in high level liquid waste treatment is crucial for managing the long-term nuclear waste disposal issues. The use of sophisticated supramolecules in a rigid framework could be the next step toward solving the long-standing problem. Here, we have investigated the possibility of separating Am3+/Eu3+ pair with cucurbit-[5]-uril (CB[5]), a macrocycle from the cucurbit-[n]-uril family, using relativistic density functional theory (DFT) based calculations. We have explored the structures, binding, and energetics of metalCB[5] complexation processes with and without the presence of counterions. Our study reveals an excellent selectivity of Eu3+ over Am3+ with CB[5] (ion exchange free energy, Delta Delta G(Am/Eu) > 10 kcal mol(1)). Both metals bind with the carbonyl portals via (5) coordination arrangement with the further involvement of three external water molecules. The presence of counterions, particularly nitrate, inside the hydrophobic cavity of CB[5], induces a cooperative cationanion binding, resulting in enhancement of metal binding at the host. The overall binding process is found to be entropy driven resembling the recent experimental observations (Rawat et al. Dalton Trans. 2015, 44, 42464258). The optimized structural parameters for Eu3+CB[5] complexes are found to be in excellent agreement with the available experimental information. To rationalize the computed selectivity trend, electronic structures are further scrutinized using energy decomposition analysis (EDA), quantum theory of atom in molecules (QTAIM), Mulliken population analysis (MPA), NalewajskiMrojek (NM) bond order, and molecular orbital analyses. Strong electrostatic iondipole interaction along with efficient charge transfer between CB[5] and Eu3+ outweighs the better degree of covalency between CB[5] and Am3+ leading to superior selectivity of Eu3+ over Am3+.