ABSTRACT The leakage of quinolone antibiotics may bring serious hazards to plants, animals, and human; thus, the detection of quinolone antibiotics is of great urgent yet remains challenging issue. Herein, two isostructural metal–organic frameworks {[(CH 3 ) 2 NH 2 ] 2 [M 3 ( μ 3 ‐O)(BPDC) 3 (TPP)]· x MeCN· y DMF} n (M = Co, x = 8, y = 1, NS‐13 ; M = Ni, x = 7, y = 1, NS‐14 ; H 2 BPDC = 4,4′‐biphenyldicarboxylic acid; TPP = 2,4,6‐tris(4‐pyridyl)pyridine), have been successfully prepared through solvothermal method. NS‐13 and NS‐14 were three‐dimensional networks built form [M 3 ( μ 3 ‐O)] 4+ clusters. Impressively, both NS‐13 and NS‐14 displayed good fluorescence response to norfloxacin, ofloxacin, and enrofloxacin with low limit of detection (LOD) and excellent recyclability, to our best knowledge, which are superior to most of reported metal–organic frameworks. Furthermore, density functional theory (DFT) calculations and fluorescence lifetime experiments uncovered the possible fluorescence probe mechanism of NS‐13 and NS‐14 toward the above‐mentioned quinolone antibiotics. This work extends the application of cluster‐based metal–organic frameworks in the detection of antibiotics.