Recently, transition metal dichalcogenides (TMDCs) have attracted significant attention in nanomedicine owing to their intriguing properties. In this study, TiS2 nanosheets, a new TMDC nanomaterial, are synthesized by a bottom-up solution-phase method and then modified with polyethylene glycol (PEG), obtaining TiS2-PEG with high stability in physiological solutions and no appreciable in vitro toxicity. Due to their high absorbance in the near-infrared (NIR) region, TiS2-PEG nanosheets could offer a strong contrast in photoacoustic imaging, which uncovers the high tumor uptake and retention of these nanosheets after systemic administration into tumor-bearing mice. We further apply TiS2-PEG nanosheets for in vivo photothermal therapy, which are able to completely eradicate the tumors in mice upon intravenous injection of TiS2-PEG followed by NIR laser irradiation. Our work indicates that TiS2 nanosheets with appropriate surface coating (e.g. PEGylation) would be a promising new class of photothermal agents for imaging-guided cancer therapy.