This study examined the mechanism through which plumbagin induces ferroptosis of colon cancer cells.CCK-8 assay was performed to examine the viability of colon cancer cells (SW480 and HCT116 cells) after they were treated with 0-, 5-, 10-, 15- and 20-μmol/L plumbagin. Colony formation assay and Transwell assay were used to examine the effects of 15-μmol/L plumbagin on the proliferation, invasive ability. The ferroptosis of SW480 and HCT116 cells and the expression of p-p53, p53 and SLC7A11 were analysed. The effects of blocking necrosis, apoptosis and ferroptosis on the anti-cancer effects of plumbagin were examined. After p53 was silenced, the effects of plumbagin on proliferation, invasion, ferroptosis and SLC7A11 expression were assessed. A tumour-bearing nude mouse model was used to examine the effects of p53 silencing and/or plumbagin on tumour growth, ferroptosis and SLC7A11 expression.Plumbagin inhibited the proliferation of SW480 and HCT116 cells and their invasive and colony-forming abilities. It increased Fe2+ levels but significantly decreased GSH and GPX4 levels. When ferroptosis was inhibited, the effects of plumbagin on colon cancer cells were significantly alleviated. Plumbagin promoted the expression and phosphorylation of p53 and inhibited the mRNA and protein levels of SLC7A11. Silencing of p53 counteracted the effects of plumbagin on the ferroptosis and biological behaviour of SW480 and HCT116 cells. In mouse models of colon cancer, silencing of p53 attenuated the tumour-suppressing effects of plumbagin as well as its inhibitory effects on the protein level of SLC7A11 and restored the expression of GSH and GPX4.Plumbagin promotes ferroptosis and inhibits cell proliferation and invasion by decreasing the protein expression of SLC7A11 through p53.© 2024 The Authors.