The first definitive high-resolution single-crystal X-ray structure for the coordination of the 1-methylimidazole (Meimid) ligand to UO2(Ac)(2) (Ac = CH3CO2) is reported. The crystal structure evidence is confirmed by IR, Raman, and UV-vis spectroscopic data. Direct participation of the nitrogen atom of the Meimid ligand in binding to the uranium center is confirmed. Structural analysis at the DFT (B3LYP) level of theory showed a conformational difference of the Meimid ligand in the free gas-phase complex versus the solid state due to small energetic differences and crystal packing effects. Energetic analysis at the MP2 level in the gas phase supported stronger Meimid binding over H2O binding to both UO2(Ac)(2) and UO2(NO3)(2). In addition, self-consistent reaction field COSMO calculations were used to assess the aqueous phase energetics of combination and displacement reactions involving H2O and Meimid ligands to UO2R2 (R = Ac, NO3). For both UO2(NO3)(2) and UO2(Ac)(2), the displacement of H2O by Meimid was predicted to be energetically favorable, consistent with experimental results that suggest Meimid may bind uranyl at physiological pH. Also, log(K-nitrate/K-Ac) calculations supported experimental evidence that the binding stoichiometry of the Meimid ligand is dependent upon the nature of the reactant uranyl complex. These results clearly demonstrate that imidazole binds to uranyl and suggest that binding of histidine residues to uranyl could occur under normal biological conditions.