Ferroptosis, an iron-dependent form of programmed cell death (PCD), has been closely linked to ischemic stroke (IS). The mechanisms of ferroptosis are primarily associated with iron metabolism, lipid peroxide metabolism, and glutathione and amino acid metabolism. The disruption of the blood-brain barrier (BBB), the release of excitatory amino acids, and inflammatory responses after IS lead to iron metabolism disorders and antioxidant system disruptions. This review discusses the effects of compounds and drugs that treat IS by modulating key molecules in ferroptosis. Key molecules such as glutathione peroxidase 4 (GPX4), cystine/glutamate exchanger xCT (SLC7A11), ferroportin (FPN), and acyl-CoA synthetase long-chain family member 4 (ACSL4) play crucial roles in ferroptosis, and their regulation offers potential therapeutic targets for IS. Additionally, the role of ferroptosis in IS is highlighted, emphasizing its exacerbating effect on IS. The review also explores the therapeutic potential of compounds targeting GPX4, SLC7A11, ACSL4, and lipoxygenase (LOX) to prevent and treat IS. Despite the progress in understanding ferroptosis and its role in IS, challenges remain in translating preclinical findings to clinical trials due to complex pathophysiological mechanisms and the need for precise dosing of agents.Ferroptosis, an iron-dependent form of programmed cell death (PCD), has been closely linked to ischemic stroke (IS). The mechanisms of ferroptosis are primarily associated with iron metabolism, lipid peroxide metabolism, and glutathione and amino acid metabolism. The disruption of the blood-brain barrier (BBB), the release of excitatory amino acids, and inflammatory responses after IS lead to iron metabolism disorders and antioxidant system disruptions. This review discusses the effects of compounds and drugs that treat IS by modulating key molecules in ferroptosis. Key molecules such as glutathione peroxidase 4 (GPX4), cystine/glutamate exchanger xCT (SLC7A11), ferroportin (FPN), and acyl-CoA synthetase long-chain family member 4 (ACSL4) play crucial roles in ferroptosis, and their regulation offers potential therapeutic targets for IS. Additionally, the role of ferroptosis in IS is highlighted, emphasizing its exacerbating effect on IS. The review also explores the therapeutic potential of compounds targeting GPX4, SLC7A11, ACSL4, and lipoxygenase (LOX) to prevent and treat IS. Despite the progress in understanding ferroptosis and its role in IS, challenges remain in translating preclinical findings to clinical trials due to complex pathophysiological mechanisms and the need for precise dosing of agents.