Significant progress is made in the treatment of metastatic colorectal cancer (mCRC) patients, however, therapeutic options remain limited for patients with mCRC. In recent years, traditional Chinese medicine (TCM) has gained significant attention. Among these, Huangqin Houpo decoction has demonstrated efficacy in mCRC treatment. Despite its promise, the active ingredients and mechanisms underlying its anticancer effects remain unclear. Using integrative pharmacological approaches, six compounds are identified as the primary active ingredients in Huangqin Houpo decoction. Among them, honokiol (H), magnolol (M), and baicalin (B) are found to exhibit a synergistic anticancer effect on CRC. The HMB combination significantly outperforms mono- or bi-agent treatments in reducing tumor growth. Furthermore, the anticancer efficacy of the HMB combination surpasses that of medium- and high-dose Huangqin Houpo decoction and the FOLFOX regimen. Notably, HMB is comparable in efficacy to the FOLFOIRI regimen. Most importantly, HMB is shown to enhance the sensitivity of CRC cells to anti-PD-1 immunotherapy in vivo. Mechanistic studies reveal that the HMB combination exerts its synergistic anticancer effects and enhances anti-PD-1 immunotherapy by inducing GSDME-dependent pyroptosis. Our study will hopefully provide a potential therapeutic strategy for mCRC patients in the future.