Room temperature ionic liquids (RTILs) represent a recent new class of solvents applied in liquid/liquid extraction based nuclear fuel reprocessing, whereas the related coordination chemistry and detailed extraction processes are still not well understood and remain of deep fundamental interest. The work herein provides a new insight of coordination and extraction of uranium(VI) with N-donating ligands, e.g., N,N'-diethyl-N,N'-ditolyldipicolinamide (Et(p)TDPA), in commonly used RTILs. Exploration of the extraction mechanism, speciation analyses of the extracted U(VI), and crystallographic studies of the interactions of Et(p)TDPA with U(VI) were performed, including the first structurally characterized UO2(Et(p)TDPA)2(NTf2) and UO2(Et(p)TDPA)2(PF6)2 compounds and a first case of crystallographic differentiation between the extracted U(VI) complexes in RTILs and in molecular solvents. It was found that in RTILs two Et(p)TDPA molecules coordinate with one U(VI) ion through the carbonyl and pyridine nitrogen moieties, while NTf2 and PF6 act as counterions. The absence of NO3 in the complexes is coincident with a cation-exchange extraction. In contrast, both the extracted species and extraction mechanisms are greatly different in dichloromethane, in which UO22+ coordinates in a neutral complex form with one Et(p)TDPA molecule and two NO3 cations. In addition, the complex formation in RTILs is independent of the cation exchange since incorporating UO2(NO3)(2), Et(p)TDPA, and LiNTf2 or KPF6 in a solution also produces the same complex as that in RTILs, revealing the important roles of weakly coordinating anions on the coordination chemistry between U(VI) and Et(p)TDPA. These findings suggest that cation-exchange extraction mode for ILs-based extraction system probably originates from the supply of weakly coordinating anions from RTILs. Thus the coordination of uranium(VI) with extractants as well as the cation-exchange extraction mode may be potentially changed by varying the counterions of uranyl or introducing extra anions.