Extracting uranium from seawater remains a formidable challenge because of its extremely low concentration of 3.3 ppb. State-of-the-art polymeric sorbents employ both amidoximate and carboxylate groups on the side chains to achieve optimal U uptake and selectivity, but little is known about the synergistic effect between the two functional groups in binding with uranyl. Herein, we simulated the binding of a model amidoximate-carboxylate bifunctional ligand with uranyl using a combination of theoretical methods. Gas-phase quantum-mechanical calculations showed a chelate binding of a η2 amidoximate and a monodentate carboxylate to uranyl. Ab initio molecular dynamics (MD) simulations in an explicit water solvation model confirmed the stability of the chelate mode. Classical MD and free-energy simulations in 0.5 M NaCl showed that the carboxylate group binds first to uranyl, leading to a loose intermediate state, and then, the amidoximate group binds, resulting in a more stable and tight chelate state. Binding of the second bifunctional ligand follows a similar process, and the two ligands prefer a trans configuration around the uranyl group. The simulated free energies indicate that the two bifunctional ligands bind with uranyl 55 kJ/mol stronger than the two ligands with only amidoximate groups. This work suggests an important synergy between amidoximate and carboxylate groups in binding uranyl.