BACKGROUND: Colorectal cancer (CRC) continues to represent a significant global public health challenge. Ferroptosis, a novel form of cell death dependent on iron and involving lipid peroxidation, has emerged as an effective strategy for treating various cancers with great potential for application. PURPOSE: This study aimed to investigate the therapeutic potential of erianin, a novel dibenzyl compound isolated from the well-known herbal medicine Dendrobium chrysotoxum Lindl, in the treatment of CRC through induction of ferroptosis. METHODS: Human CRC HCT116 and SW480 cells were employed for in vitro investigations, while an AOM/DSS CRC animal model was established for in vivo experiments. RESULTS: The results demonstrated that erianin effectively inhibited the growth of CRC cells and suppressed tumorigenesis in the AOM/DSS CRC animal model. Erianin induced ferroptosis in CRC cells as evidenced by a significant increase in intracellular Fe CONCLUSION: Erianin demonstrates the potential to inhibit CRC by inducing ferroptosis through accelerating the ubiquitination and degradation of GPX4, indicating its promise as a therapeutic candidate against CRC.