<p>Uranium extraction from seawater is a promising strategy to secure sustainable nuclear fuel resources, yet it faces major challenges due to the extremely low uranium concentration (≈ 3.3 ppb), high ionic strength, and strong stability of the uranyl-tricarbonate complex [UO₂(CO₃)₃]⁴⁻. This review summarizes recent advances in ligand design for selective uranyl (UO₂²⁺) capture, emphasizing the correlation between electronic structure, coordination geometry, and extraction performance. Quantum-chemical and spectroscopic studies have established that the η²(N, O) coordination mode in amidoxime (AO) ligands forms mixed σ–π hybrid covalent bonds with uranyl 5f/6d orbitals, weakening axial U = O bonds and strengthening equatorial interactions. Rational molecular strategies include (i) electron-density modulation, (ii) internal hydrogen bonding for geometric fixation, (iii) proton-relay-assisted carbonate dissociation, and (iv) N-alkylation for U/V selectivity. Beyond AO, ligands such as Saldian (N₃O₂) and phenanthroline dicarboxylates employ rigid π frameworks and cooperative chelation to achieve high stability (log β ≈ 28), while biomolecule-derived systems like SUP proteins and DNA hydrogels exhibit femtomolar uranyl affinity. Six design parameters—including electron-density tuning, internal hydrogen bonding, proton-relay activation, coordination directionality, π-resonance control, and surface optimization—now define a predictive paradigm for uranyl–ligand coordination. The integration of density-functional theory, advanced spectroscopy, and machine-learning-driven inverse design enables rapid identification of high-affinity, seawater-resilient ligands and guides the creation of electronically tuned materials for next-generation, durable, and sustainable uranium-extraction technologies.</p>