Copper sulfide nanoparticles (CuS NPs) have garnered significant attention in photothermal therapy (PTT) owing to their facile synthesis, biodegradability, stability, and excellent photothermal conversion efficiency. Nonetheless, their potential toxic effects have restricted their application. This research focuses on the encapsulation of CuS NPs with the biocompatible polymer poly(lactic-co-glycolic acid) (PLGA) to enhance their biocompatibility, thereby improving the efficacy and safety of PTT in the treatment of triple-negative breast cancer (TNBC). Three distinct methods, namely aqueous phase loading method, oil phase loading method, and "in situ reduction" method were employed to synthesize PLGA-coated CuS (CuS@PLGA) NPs to optimize the encapsulation rate of CuS. Among these, the CuS@PLGA NPs fabricated via the "in situ reduction" method demonstrated the highest encapsulation efficiency for CuS, achieving a rate of (90.4 ± 3.3)%. The resulting CuS@PLGA NPs exhibited high stability, excellent photothermal effect, and good tumor-targeting ability. Moreover, CuS@PLGA NPs demonstrated enhanced anti-tumor efficacy and biocompatibility compared to CuS NPs in both in vitro and in vivo experiments. Consequently, this study offers an effective and safety strategy for PTT treatment of TNBC.