2D covalent organic frameworks (2D COFs) have been recognized as a novel class of photoactive materials owing to their extended π‐electron conjugation and high chemical stabilities. Herein, a new covalent organic framework (Tph‐BDP) is facilely synthesized by using a porphyrin derivative and an organic dye BODIPY derivative (5,5‐difluoro‐2,8‐diformyl‐1,3,7,9‐tetramethyl‐10‐phenyl‐5H‐dipyrrolo1,2‐c:2′,1′‐f1,3,2diazabori‐nin‐4‐ium‐5‐uide) as monomers for the first time, and their unique photosensitive properties endow them excellent simulated oxidase activity under 635 nm laser irradiation that can catalyze the oxidation of 3,3′,5,5′‐tetramethylbenzidine (TMB). Further findings demonstrate that the presence of uranium (UO22+) can coordinate with imines of the oxidation products of TMB, thus modulating the charge transfer process of the colored products accompanied with intensive aggregation and remarkable color fading. This research provides a preparation strategy for COFs with excellent photocatalytic properties and nanozyme activity, and broadens the applications of the simple colorimetric methods for sensitive and selective radionuclide detection. A new covalent organic framework is facilely synthesized and its unique photosensitive property endows excellent simulated oxidase activity that can catalyze the oxidation of 3,3′,5,5′‐tetramethylbenzidine (TMB). The presence of uranium can coordinate with imines of the oxidation products of TMB, thus modulating the charge transfer process of the colored products accompanied with intensive aggregation and remarkable color fading.