Indium, a low melting point metal, is well-known for constructing eutectic gallium−indium liquid metal. However, unlike liquid metal nanoparticles, the biomedical applications of metallic indium nanoparticles (In NPs) remain in their infancy. Herein, an ultrasound-assisted liquid-reduction synthesis strategy was developed to prepare PEGylated In NPs, which were then used as a highperformance contrast agent for enhancing multiwavelength photoacoustic imaging and second near-infrared (NIR-II) photothermal therapy of the 4T1 breast tumor. The obtained In NPs depicted remarkable optical absorption from the first nearinfrared (NIR-I) to NIR-II region and a high photothermal conversion efficiency of 41.3% at 1064 nm, higher than the majority of conventional NIR-II photothermal agents. Upon injection into the tumor, the photoacoustic intensities of the tumor section post-injection were obviously increased by 2.59-, 2.62-, and 4.27-fold of those of pre-injection by using excitation wavelengths of 750, 808, and 970 nm, respectively, depicting an excellent multiwavelength contrast capability of photoacoustic imaging. In addition, efficient ablation of the 4T1 tumor was achieved through the photothermal performance of PEGylated In NPs under NIR-II laser irradiation. Importantly, as the widely used element in the clinic, In NPs were highly biocompatible in vitro and in vivo. Therefore, this work pioneered the biomedical applications of PEGylated In NPs for cancer diagnosis and treatment.