Photodynamic therapy (PDT), an emergent noninvasive cancer treatment, is largely dependent on the presence of efficient photosensitizers (PSs) and a sufficient oxygen supply. However, the therapeutic efficacy of PSs is greatly compromised by poor solubility, aggregation tendency, and oxygen depletion within solid tumors during PDT in hypoxic microenvironments. Despite the potential of PS-based metal-organic frameworks (MOFs), addressing hypoxia remains challenging. Boron dipyrromethene (BODIPY) chromophores, with excellent photostability, have exhibited great potential in PDT and bioimaging. However, their practical application suffers from limited chemical stability under harsh MOF synthesis conditions. Herein, we report the synthesis of the first example of a Zr-based MOF, namely, 69-L2, exclusively constructed from the BODIPY-derived ligands via a single-crystal to single-crystal post-synthetic exchange, where a direct solvothermal method is not applicable. To increase the PDT performance in hypoxia, we modify 69-L2 with fluorinated phosphate-functionalized methoxy poly(ethylene glycol). The resulting 69-L2@F is an oxygen carrier, enabling tumor oxygenation and simultaneously acting as a PS for reactive oxygen species (ROS) generation under LED irradiation. We demonstrate that 69-L2@F has an enhanced PDT effect in triple-negative breast cancer MDA-MB-231 cells under both normoxia and hypoxia. Following positive results, we evaluated the in vivo activity of 69-L2@F with a hydrogel, enabling local therapy in a triple-negative breast cancer mice model and achieving exceptional antitumor efficacy in only 2 days. We envision BODIPY-based Zr-MOFs to provide a solution for hypoxia relief and maximize efficacy during in vivo PDT, offering new insights into the design of promising MOF-based PSs for hypoxic tumors.