Solvent extraction studies of UO22+ were carried out using N,N'-dimethyl-N,N'-dibutylmalonamide (DMDBMA), N,N,N',N'-tetrabutylmalonamide (TBMA), and N,N,N',N'-tetraoctylmalonamide (TOMA) dissolved in three room temperature ionic liquids (RTILs) of 1-alkyl-3-methylimidazolium bis(trifluoromethane)sulfonamide ([C(n)mim][Tf2N], n = 4,6,8). At lower acidity, the extraction of UO22+ carried out in RTIL was found to be much more efficient than in the conventional molecular diluents, while this advantage diminishes at higher acidity. The alkyl chain length of the RTILs plays an important role on the extraction performance. The effect of concentration of three diamides and nitric acid on extraction performance was also investigated. The extraction mechanism using RTILs as the diluent was deduced by the slope analysis and extraction experiment, and a cation-exchange mechanism at lower acidity and a neutral solvation mechanism at higher acidity were proposed. Density functional theory method was used to characterize the key species of the coordination complexes of UO22+ with the three malonamide (MA) ligands in terms of geometry, Mayer bond order (MBO), binding energy, interface exchange reaction, stepwise mechanism, and quantum theory of atom-in-molecule (QTAIM) topological analysis.