Two-dimensional Cd-MOF/Tb3+ (Cd-MOF = [Cd (μ-2,3-pdc) (H2O)3]n (2,3-pdc = 2,3-pyridine dicarboxylic acid)) fluorescent nanosheets with the thickness of 1.4 nm were successfully synthesized by a simple solution route with subsequent ultrasonic exfoliation at room temperature. It was found that as-obtained Cd-MOF/Tb3+ ultrathin nanosheets could be homogeneously dispersed in aqueous system to form a sol with excellent stability. Also, the fluorescence intensity of nanosheets remarkably increased to almost 12 times higher than that of Cd-MOF/Tb3+ microsheets before exfoliation. Further investigations uncovered that the above strong fluorescence of Cd-MOF/Tb3+ nanosheets could be highly sensitively quenched by Cefixime antibiotic in aqueous solution without interference from other antibiotics, amino acids and pesticides. Hence, the as-obtained ultrathin Cd-MOF/Tb3+ nanosheets could be prepared as a highly selective and sensitive fluorescence probe for the detection of Cefixime in aqueous system. Compared with the bulk Cd-MOF/Tb3+ sensor, the Cd-MOF/Tb3+ ultrathin nanosheets sensor exhibited a far lower detection limit down to 26.7 nM for CFX. Also, the as-obtained nanosheets sensor presented satisfactory recovery ranging from 98.07% to 103.01% and acceptable repeatability (RSD