No-carrier-added (NCA) 177 Lu is one of the most interesting nuclides for endoradiotherapy. With the dramatically rapid development of radiopharmaceutical and nuclear medicine, there is a sharp increase in the radionuclide supply of NCA 177 Lu, which has formed a great challenge to current radiochemical separation constituted on classical materials. Hence, it is of vital importance to design and prepare new functional materials able of recovering 177 Lu from an irradiated target with excellent efficacy. In this work, we proposed to apply noncovalent interactions to regulate the porous properties of covalent organic frameworks (COFs) by tuning the branched chain, rendering related covalent hosts different encapsulation abilities toward a flexible guest, 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester (P507). More interestingly, we found that the noncovalent interaction has a great effect on the host-guest complexes, which can achieve efficient NCA 177 Lu separation with high recovery (95.97%). A systematic mechanism combined with experimental and theoretical investigations has confirmed that the noncovalent interactions between COFs and P507 play a preeminent role in adjusting the macroscopic properties of the host-guest complexes. This work not only uncovers that noncovalent interactions can affect the basic properties of covalent organic bonded materials but also provides a strategy for the design and preparation of other new moieties with specific functionalities.