Recently, the emerging chemotherapy (CDT) has provided a new biocompatibility pathway for cancer therapy. Among them, Cu-based nanocatalysts with good biocompatibility and Fenton-like catalytic efficiency are considered to be a promising approach for enhancing CDT and CDT-involved multimodal synergies to improve the effectiveness of catalytic cancer therapy. Meanwhile, the emerging in situ therapy strategy promoted by Cu-based nanocatalysts has proven to exhibit attractive clinical application potential in replacing traditional chemotherapy and radiotherapy for cancer therapy with significant toxic side effects. In this work, the recent progress of various Cu-based nanocatalysts in cancer therapy was reviewed, especially the remarkable achievements in the catalytic treatment of cancer in the tumor microenvironment using CDT and CDT-involved multimodal synergies. In addition, the development expectations and challenges of Cu-based nanocatalysts in the field of cancer therapy were briefly summarized and discussed. We expect that this review will contribute to the development of Cu-based nanocatalysts for cancer therapy.