The lack of sensitive detection techniques and agents for early-stage tumors, which are characterized by small size, juvenile blood vessels and scarce secreted markers, has hampered timely cancer therapy and human well-being. Herein, the natural product pyropheophorbide-a (PPa) and FDA-approved Pluronic F127 are organized to develop F127-PPa nanomicelles with favorable size, red-shifted fluorescence and decent biocompatibility. After intravenous (i.v.) injection, the F127-PPa nanomicelles could not only accurately identify early-stage xenografted tumors, but also sensitively detect cancer metastasis in lungs through near-infrared (NIR) fluorescence imaging. The fluorescence signals are consistent with radionuclide imaging, photoacoustic (PA) imaging and bioluminescence imaging of tumors, consolidating the reliability of using F127-PPa nanomicelles for sensitive cancer diagnosis in a non-invasive and low-cost manner. Moreover, the fluorescence intensity of small tumors is linearly correlated with the tumoral mass ranging from 10 to 120 mg with a fluorescence coefficient of 4.5 × 107 mg-1. Under the guidance of multimodal imaging, the tumors could be thoroughly eradicated by F127-PPa under laser irradiation due to efficient reactive oxygen species (ROS) generation. These findings may provide clinically translatable agents and strategies for sensitive diagnosis of early-stage tumors and timely cancer therapy.