AbstractFerroptosis is a novel form of programmed cell death and is considered to be a druggable target for colorectal cancer (CRC) therapy. However, the role of ferroptosis in CRC and its underlying mechanism are not fully understood. In the present study we found that a protein enriched in the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3), was overexpressed in human CRC tissue and in several CRC cell lines. The expression of GOLPH3 was significantly correlated with the expression of ferroptosis‐related genes in CRC. The overexpression of GOLPH3 in Erastin‐induced Caco‐2 CRC cells reduced ferroptotic phenotypes, whereas the knockdown of GOLPH3 potentiated ferroptosis in HT‐29 CRC cells. GOLPH3 induced the expression of prohibitin‐1 (PHB1) and prohibitin‐2 (PHB2), which also inhibited ferroptosis in Erastin‐treated CRC cells. Moreover, GOLPH3 interacted with PHB2 and nuclear factor erythroid 2‐related factor 2 (NRF2) in Caco‐2 cells. These observations indicate that GOLPH3 is a negative regulator of ferroptosis in CRC cells. GOLPH3 protects these cells from ferroptosis by inducing the expression of PHB1 and PHB2, and by interacting with PHB2 and NRF2.