Although being applied as photosensitizers for photodynamic therapy, covalent organic frameworks (COFs) fail the precise fluorescence imaging in vivo and phototherapy in deep‐tissue, due to short excitation/emission wavelengths. Herein, we propose the first example of NIR‐II emissive and benzobisthiadiazole‐based COF‐980. Comparing to its ligands, the structure of COF‐980 could more efficiently reducing the energy gap (ΔES1‐T1) between the excited state and the triplet state to enhance photodynamic therapy efficiency. Importantly, COF‐980 demonstrates high photostability, good anti‐diffusion property, superior ROS generation efficiency, promising imaging ability and ROS production in deep tissue (ཞ8 mm). In vitro results reveal COF‐980 combined with laser irradiation could trigger larger amount of intracellular ROS to high‐efficiently induce cancer cell death. Notably, COF‐980 NPs precisely enables PDT guided by NIR‐II fluorescence imaging that effectively inhibit the 4T1 tumor growth with negligible adverse effects. This study provides a universal approach to developing long‐wavelength emissive COFs and exploits its applications for biomedicine.This article is protected by copyright. All rights reserved