Ferroptosis, a unique form of nonapoptotic-regulated cell death caused by overwhelming lipid peroxidation, represents an emerging tumor suppression mechanism. Growing evidence has demonstrated that cell metabolism plays an important role in the regulation of ferroptosis. Specifically, the association between methionine metabolism and ferroptosis remains undefined. We performed in vitro and in vivo experiments to evaluate the influence of methionine metabolism on ferroptosis sensitivity. Pharmacological and genetic blockade of the methionine cycle was utilized and relevant molecular analyses were performed. We identified MAT2A as a driver of ferroptosis resistance. Mechanistically, MAT2A mediates the production of S-adenosylmethionine (SAM), which upregulates ACSL3 by increasing the trimethylation of lysine-4 on histone H3 (H3K4me3) at the promoter area, resulting in ferroptosis resistance. Collectively, these results established a link between methionine cycle activity and ferroptosis vulnerability in gastric cancer. Display omitted •Ferroptosis, a new form of programmed cell death caused by overwhelming lipid peroxidation, has gained a lot of interest in the field of cancer therapeutics.•However, few studies have thoroughly investigated the association between methionine metabolism and ferroptosis.•MAT2A mediates the production of S-adenosylmethionine (SAM), which upregulates ACSL3 by increasing the trimethylation of lysine-4 on histone H3 (H3K4me3) at the promoter area, resulting in ferroptosis resistance.