Colorectal cancer (CRC) is a common gastrointestinal malignancy with incidence and mortality rates ranking among the highest of all cancers, and patients generally have a poor prognosis. Current standard clinical treatments primarily include surgical resection, radiotherapy, and chemotherapy; however, surgery is only applicable to localized lesions and offers limited efficacy for metastatic or advanced-stage patients. Although chemotherapeutic agents such as 5-fluorouracil, capecitabine, and oxaliplatin can inhibit tumor progression, they are frequently associated with severe adverse effects. In recent years, traditional Chinese medicine and its active components have demonstrated potential in antitumor research through multi-target, multi-pathway synergistic effects, with relatively lower toxicity and side effects. Ponicidin (PON), a diterpenoid compound extracted from the traditional Chinese herb Rabdosia rubescens, has been confirmed to exert significant growth-inhibitory effects against various malignancies. Nevertheless, the specific molecular mechanisms underlying its action in colorectal cancer remain incompletely elucidated. This study aims to systematically evaluate the antitumor efficacy of PON against colorectal cancer and to deeply reveal its related molecular mechanisms, thereby providing experimental evidence for the further development and clinical application of PON.