An excellently stable TbIII-organic framework, [TbL·2H2O]n (complex 1), has been successfully synthesized through an assembly process. By virtue of its excellent water stability and strong green luminescence, complex 1 has been considered and applied as a reversible multi-responsive luminescent sensor for Fe3+, Cr2O72-, and nitrofurantoin (NFT) aqueous solutions. Complex 1 not only exhibits outstanding detection effects with high selectivity and sensitivity, but also shows remarkable cycling and regeneration abilities. The Ksv values of complex 1 for Fe3+, Cr2O72-, and NFT are 2.27 × 104, 2.31 × 104, and 5.26 × 104 M-1 in water systems, respectively. More importantly, complex 1 can accurately monitor NFT in real bovine serum samples via luminescence quenching detection.