Photodynamic therapy (PDT) has emerged as an important minimally invasive tumor treatment technology. The use of metal–organic frameworks (MOFs) that integrate porphyrin photosensitizers into the ordered porous structure has opened up an attractive way to inhibit the photoinduced quenching of the photosensitizer and effectively enhance PDT. However, as a reactive oxygen species (ROS)-based therapy, the efficacy of PDT is still inhibited by the hypoxic tumor microenvironment. Here, we propose that the fabrication of a novel multifunctional MOF platform with both clinically available iron catalase-like active centers and near-infrared photosensitive molecules with a higher excitation wavelength can effectively improve the photodynamic performance of this type of photosensitive platform. To overcome the challenge of lack of water-stable iron-based MOFs simultaneously containing large open channels and high density redox metal centers, we for the first time, using a multicarboxyl modification strategy, integrated high density Fe-based catalytic centers and the clinically available ICG molecule into the same MOF and obtained a novel self-oxygen generation enhanced photodynamic platform ICG ⊂ UMOF@FeOOH (IMF). The effectively enhanced PDT performance of this novel platform based on a multifunctional MOF under hypoxia conditions was successfully verified using HeLa cells and in vivo anti-tumor experiments.