Near-infrared (NIR)-absorbing metal-based nanomaterials have shown tremendous potential for cancer therapy, given their facile and controllable synthesis, efficient photothermal conversion, capability of spatiotemporal-controlled drug delivery, and intrinsic imaging function. Tantalum (Ta) is among the most biocompatible metals and arouses negligible adverse biological responses in either oxidized or reduced forms, and thus Ta-derived nanomaterials represent promising candidates for biomedical applications. However, Ta-based nanomaterials by themselves have not been explored for NIR-mediated photothermal ablation therapy. In this work, an innovative Ta-based multifunctional nanoplatform composed of biocompatible tantalum sulfide (TaS2) nanosheets (NSs) is reported for simultaneous NIR hyperthermia, drug delivery, and computed tomography (CT) imaging. The TaS2 NSs exhibit multiple unique features including (i) efficient NIR light-to-heat conversion with a high photothermal conversion efficiency of 39%, (ii) high drug loading (177% by weight), (iii) controlled drug release triggered by NIR light and moderate acidic pH, (iv) high tumor accumulation via heat-enhanced tumor vascular permeability, (v) complete tumor ablation and negligible side effects, and (vi) comparable CT imaging contrast efficiency to the widely clinically used agent iobitridol. It is expected that this multifunctional NS platform can serve as a promising candidate for imaging-guided cancer therapy and selection of cancer patients with high tumor accumulation.