Increasing researches have demonstrated that targeting ferroptosis might be a new conceptual avenue to treat colorectal cancer (CRC). Mollugin is a phytochemical isolated from Rubia cordifolia L. with antitumor activity. However, whether ferroptosis mediates the antitumor activity of mollugin in CRC has not been explored. Our study aims to investigate the antitumor and pro-ferroptosis effects, and mechanisms of mollugin in CRC. We found that mollugin led to ferroptosis in CRC cells, resulting in reduced GSH level and elevated levels of ROS, Fe²⁺, and MDA. Mollugin treatment caused obvious decrease in cell viability and proliferation in CRC cells, which were aggravated by ferroptosis inducer erastin and attenuated by ferroptosis inhibitor ferrostatin-1. Tumor xenografts experiments proved that mollugin suppressed the tumor growth, while treatment with ferrostatin-1 attenuated the antitumor activity of mollugin in vivo. Integrated bioinformatics analysis showed that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) was highly expressed in CRC tissues and indicated poor prognosis. Further investigation indicated that the IGF2BP3/glutathione peroxidase 4 (GPX4) axis was involved in mollugin-regulated ferroptosis in CRC. In conclusions, Mollugin suppresses proliferation and drives ferroptosis of CRC cells by inhibiting the IGF2BP3/GPX4 axis, suggesting that mollugin may be a potential therapeutic option for CRC.