Natural melanin has been demonstrated to be a biocompatible and efficient nanoagent for the photothermal ablation of tumors, but their practical applications are limited due to their lack of typical imaging functions (CT, MRI, etc.). Thus, to achieve multifunctional melanin-based nanoagents for imaging-guided therapy, for the first time, herein, we report the in situ growth of Au nanoparticles on natural melanin as a model through a simple and safe method. The as-synthesized samples are composed of melanin nanoparticles (diameter: ∼120 nm) whose surface are decorated by small Au nanoparticles with an adjustable size ranging from ∼10 to ∼40 nm. These Au-decorated melanin (Au-M) nanocomposites exhibit satisfactory near infrared (NIR) photoabsorption and high photothermal conversion efficiency of 42.3%. Furthermore, the Au-M nanocomposites have a high X-ray attenuation coefficient and exhibit excellent biocompatibility. When the Au-M solutions were injected into the tumor of a mouse, the tumor could be detected by X-ray computed tomography (CT), photoacoustic (PA) and thermal imaging, and then be thermally ablated under the illumination of an 808 nm laser. Therefore, these Au-M nanocomposites have great potential as a novel multifunctional and biocompatible nanoagent for imaging-guided photothermal tumor ablation.