Molybdenum disulfide (MoS2), as a transition metal dichalcogenide, has attracted tremendous attention owing to its remarkable electronic, physical, and chemical properties. In this study, based on the energy-converting nanomedicine, we report multifunctional two-dimensional (2D) MoS2 nanosheets with inherent plasmonic property and piezocatalytic activity for imaging-guided synergistic tumor therapy. MoS2 nanosheets display strong plasmon resonances in the near-infrared (NIR) region, especially in the second NIR biological window, possessing a notable light energy to heat effect under 1064 nm laser irradiation, which not only serves as a robust photothermal agent for cancer cell ablation but also acts as a contrast-enhanced agent for thermal imaging and photoacoustic imaging. Meanwhile, MoS2 nanosheets feature a remarkable piezotronic effect, exhibiting mechanical vibration energy to electricity under the stimulation of ultrasound-mediated microscopic pressure for reactive oxygen species generation to further kill cancer cells. The new function for old materials may open up the in-depth exploration of MoS2-based functional biomaterials in the future clinical application of imaging-guided photothermal and piezocatalytic synergetic treatment.