The urgent need for efficient extraction of radio-strontium (Sr) from complex aquatic environments arises from its extreme radiotoxicity to both ecosystems and human health, which remains a significant challenge. In this study, we developed an ultrathin 2D Cu-MOF-COOH nanosheet with cage-like cavities for strontium separation. Incorporating the permanent cavity structures on MOF nanosheet can fully utilize its structural characteristics of largely exposed surface area and accessible adsorption sites in pollutant removal, and the comprehensive interactions between pollutants with the active sites and cavities on the exposed surfaces can achieve highly selective and efficient capture. Consequently, Cu-MOF-COOH nanosheet exhibited superior capture performances, in terms of removal kinetics, selectivity, and uptake capacity, which are obviously better than its 3D counterpart. Moreover, it demonstrated an ultra-high selectivity and anti-interference ability, enabling efficient Sr2+ removal even in the presence of large excesses of Ca2+, Ba2+, and other alkaline and alkali earth metal ions. Remarkable anti-interference performances were further validated by its practical applications in diverse real-world samples including lake water, simulated groundwater, and radioactive wastewater, with Sr2+ removal efficiencies exceeding 91%. Those exceptional extraction performances can be attributed to the synergistic interactions between the accessible active sites (carboxylate groups) and cage-like cavities with Sr2+, which was clarified through a series of characterizations and theory calculations. This study presents a highly promising material for the separation of radioactive Sr2+ from aqueous solution and, more importantly, offers a novel strategy for the rational design of ultrathin MOF nanosheets with cavity structures, which holds great potential for expanding the applications of MOF nanosheets.