Abstract As the global nuclear industry expands rapidly, uranium extraction from seawater has garnered significant attention due to its immense resource potential. However, the ultra‐low uranium concentration and complex environment in seawater pose significant challenges to uranium extraction, which encourages the advancement of high‐performance adsorbents for uranium. Herein, three amidoxime‐functionalized defective metal–organic frameworks (UiO‐66‐3BA‐AO, UiO‐66‐4BA‐AO, and UiO‐66‐AA‐AO) are successfully constructed via a ligand regulation strategy for selective and highly efficient uranium extraction from seawater. The engineered defect structure significantly enhances the uranium adsorption capacity and adsorption kinetics of the three adsorbents. Particularly, UiO‐66‐3BA‐AO reaches an exceptional saturated adsorption ability of 904.1 mg g −1 and obtains the uranium adsorption equilibrium in 90 min. Meanwhile, UiO‐66‐3BA‐AO extracts as high as 26.9 mg g −1 uranium from pristine seawater in 4 weeks. UiO‐66‐3BA‐AO also demonstrates outstanding selectivity, excellent recyclability, great antibacterial ability and facile loading onto different carriers, which verifies its significant practical potential for uranium extraction from seawater. Additionally, the uranium adsorption mechanisms are systematically examined at the molecular level. This study will aid in the design of novel uranium adsorbents and broaden the utilization of metal–organic frameworks (MOFs) in water treatment.