Ferroptosis is involved in the drug resistance mechanisms of some tumors. The present study aimed to explore the role of tissue inhibitor of matrix metalloprotease 1 (TIMP1) in sorafenib-triggered ferroptosis in colorectal cancer (CRC).HCT-8 CRC cell lines were generated that were sorafenib-resistant or that under- or overexpressed TIMP1. The levels of reactive oxygen species (ROS), iron, and malondialdehyde (MDA) were compared across the different cell lines. The half-maximal inhibitory concentration of sorafenib against the different lines was determined based on cell viability. Expression of ferroptosis-related genes and the corresponding proteins was determined by quantitative RT-PCR or western blotting. Results: TIMP1 overexpression induced sorafenib resistance in HCT-8 cells. TIMP1 knockdown repressed the activation of the PI3K/Akt pathway and reduced levels of glutathione peroxidase 4 (GPX4), enhancing sorafenib-induced ferroptosis. This led to accumulation of ROS, iron, and MDA. Giving sorafenib and the GPX4 inhibitor RSL3 to sorafenib-resistant HCT-8 cells induced ferroptosis, leading to elevated levels of iron and lipid peroxides, ultimately reducing cell viability. TIMP1 depletion in CRC cells enhances sorafenib-triggered ferroptosis by reducing PI3K/Akt axis signal transduction.The combination of sorafenib and GPX4 inhibitors such as RSL3 may be a promising therapy against CRC.