Effective treatment of colorectal cancer is important to improve the quality of life for patients, which however remains a great challenge in the clinic. Herein, we report the construction of a composite hydrogel that can modulate the tumor redox microenvironment for enhanced sonodynamic therapy (SDT) of colorectal cancer. Such composite hydrogels consist of sonosensitizer protoporphyrin IX (PpIX)-conjugated manganese oxide (MnO2) nanoparticles and a glutathione (GSH) inhibitor after Ca2+ induced in situ gelation in the tumor site. In the acidic tumor microenvironment, MnO2 nanoparticles can produce oxygen to relieve hypoxia and thus amplify the generation of reactive oxygen species (ROS) via the SDT effect. Meanwhile, the GSH inhibitor blocks the intracellular synthesis of GSH, thus leading to further enhanced SDT action. As such, composite hydrogel-mediated enhanced SDT can obviously inhibit the growth of subcutaneous colorectal cancer in mouse models. This study thus offers a tumor microenvironment modulating platform for enhanced therapy of colorectal cancer.