Stimuli‐responsive nanomedicines have become a recent research focus as a candidate for cancer treatment because of their effectiveness, sensibility, and minimal invasiveness. In this work, a novel nanosystem is developed based on Cu_2−xS@MnS core–shell nanoparticles (CSNPs) in which the Cu_2−xS core serves as a photosensitizer to generate hyperthermia and reactive oxygen species (ROS), and the MnS shell is used in H₂O₂‐responsive O₂ production. Cu_2−xS@MnS CSNPs with an independent core and shell ratio are synthesized by a controllable hot‐injection method, resulting in an optimal photothermal (PT) effect with a PT conversion efficiency of up to 47.9%. An enhanced photodynamic (PD) effect also occurs in an H₂O₂ environment. More significantly, in vivo experiments demonstrate that Cu_2−xS@MnS CSNPs can mediate tumor shrinkage in both HeLa tumor cell line‐derived xenograft (CDX) and head and neck squamous cell carcinoma (HNSCC) patient‐derived xenograft (PDX) models, with the capability of being used as a T1‐enhanced magnetic resonance (MR) contrast agent. These results suggest the great potential of as‐prepared Cu_2−xS@MnS CSNPs as photo/H₂O₂‐responsive therapeutic‐agents against tumors, even in a complicated and heterogeneous environment, thus promoting the clinical translation of nanomedicine.