Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening disorders with a high risk of mortality. Astaxanthin (AST) is a supernatural antioxidant that has been extensively studied due to its role in immunomodulation, oxidative stress, and lipid peroxidation. However, the association between ferroptosis and AST is not well understood. The purpose of this study is to explore the regulatory role of AST on ferroptosis in lipopolysaccharide (LPS)-induced ALI. Methods: We established an MLE-12 cell injury model and a mouse ALI model by treating with LPS. The levels of IL-6, TNF-α, and IL-1β in the mouse serum were measured using an enzyme-linked immunosorbent assay. Moreover, immunohistochemical, immunofluorescence, western blot, and quantitative real-time polymerase chain reaction analyses were conducted to examine the effects of AST and ferrostatin-1. Results: We discovered that AST pretreatment greatly alleviated LPS-induced lung injury and inhibited ferroptosis, which was demonstrated by a decrease in the accumulation of malondialdehyde and Fe2+ and an increase in the levels of glutathione and glutathione peroxidase 4 in the lung tissues of ALI mice and MLE-12 cells. Additionally, we found that AST also evidently suppressed ferritinophagy by upregulation of ferritin and downregulation of nuclear receptor co-activator 4 (NCOA4) in MLE-12 cells. Conclusions: AST pretreatment could lead to a relief of LPS-induced ALI, perhaps via suppressing ferroptosis, and could also reduce unstable iron accumulation by inhibiting NCOA4-mediated ferritin phagocytosis from mitigating lipid peroxidation and ferroptosis in lung epithelial cells.