Photothermal therapy (PTT) has become one of the most effective methods for tumor treatment. With the development of medicine, studies focusing primarily on therapeutic and diagnostic agents with desirable biocompatibility, targeting and stability are still of great significance. Heteropoly blue (HPB) is an ideal photothermal therapy agent (PTA) with decent photothermal conversion efficiency. Covalent organic frameworks (COFs) are considered to be good carriers with excellent biocompatibility. Due to their superior characteristics, such as being adjustable, and having high thermal stability and porous structures, COFs have been broadly applied in various fields. In this study, HPB was successfully in situ loaded into a COF via a one-pot method. The resultant HPB@COF platform exhibited desirable biocompatibility, pH-responsive release properties and high tumor inhibition efficiency, which can be used for PTT to effectively inhibit tumor growth. Our work provides a valuable paradigm for the fabrication of safer and effective HPB@COF NPs for future pH-responsive photothermal therapy.