Uranium is a serious radioactive contaminant that can easily migrate into groundwater and surface water, posing a deadly threat to human health. Despite the development of various materials for detecting uranyl ions in water, rational design and synthesis of new uranium sensors with sensitivity, selectivity, and fast response remain challenging. Herein, we demonstrate a novel strategy for obtaining highly sensitive and selective UO22+ sensors by constructing heterometallic metal–organic framework with both an anionic skeleton and abundant chelating sites. Namely, the first anionic Na/Eu heterometallic metal–organic framework (Na/Eu-MOF) based UO22+ sensor is successfully synthesized by using sodium salt and europium salt as reactants, and abundant ether groups were introduced into its porous structure as chelating Lewis basic sites. Beneficial from the synergistic effect between the anionic skeleton and the chelating sites, Na/Eu-MOF achieved rapid, selective adsorption and fluorescence quenching toward uranyl ion. The detection limits of Na/Eu-MOF in deionized and lake water were determined to be 49.7 nM and 113.0 nM, respectively, which are lower than the maximum concentration of 130.0 nM in drinking water proposed by the United States Environmental Protection Agency, indicating potential environmental applications. The detection capability of Na/Eu-MOF is attributed to the combination system of energy competition and interactions between UO22+ ions and Na/Eu-MOF. This work offers a feasible strategy to construct an anionic heterometallic metal–organic framework with chelating sites for uranyl detection in an aqueous solution.