Fabrication of clinically translatable nanoparticles (NPs) as photothermal therapy (PTT) agents against cancer is becoming increasingly desirable, but still challenging, especially in facile and controllable synthesis of biocompatible NPs with high photothermal efficiency. A new strategy which uses protein as both a template and a sulfur provider is proposed for facile, cost-effective, and large-scale construction of biocompatible metal sulfide NPs with controlled structure and high photothermal efficiency. Upon mixing proteins and metal ions under alkaline conditions, the metal ions can be rapidly coordinated via a biuret-reaction like process. In the presence of alkali, the inert disulfide bonds of S-rich proteins can be activated to react with metal ions and generate metal sulfide NPs under gentle conditions. As a template, the protein can confine and regulate the nucleation and growth of the metal sulfide NPs within the protein formed cavities. Thus, the obtained metal sulfides such as Ag S, Bi S , CdS, and CuS NPs are all with small size and coated with proteins, affording them biocompatible surfaces. As a model material, CuS NPs are evaluated as a PTT agent for cancer treatment. They exhibit high photothermal efficiency, high stability, water solubility, and good biocompatibility, making them an excellent PTT agent against tumors. This work paves a new avenue toward the synthesis of structure-controlled and biocompatible metal sulfide NPs, which can find wide applications in biomedical fields.