Aim To investigate the effect of hypobaric hypoxia on macrophage necroptosis and atherosclerotic plaque instability and explore the underlying mechanisms. Methods Mouse bone marrow-derived macrophages were isolated and cultured, and divided into control group (21% oxygen concentration) and hypoxia group (3% oxygen concentration). After 48 hours, cell necroptosis was detected, and the expression of cell necroptosis related proteins was determined by Western blot. Healthy male ApoE－/－ mice were randomly divided into control group and hypobaric hypoxia group. After the intervention for 16 weeks, the plasma lipids and inflammatory cytokines were measured, the areas of atherosclerotic plaque and necrotic core were evaluated by HE staining. The content of plaque collagen was detected by Masson staining. The number of macrophages in the plaque and the expression of necrotic apoptosis related proteins were detected by immunohistochemical staining and Western blot. Results Hypoxia induced increased necrotic apoptosis of macrophages (P＜0.01), while necroptotic inhibitor necrostatin-1 (Nec-1) reduced hypoxia induced cell death (P＜0.05); hypoxia leads to a decrease in the expression of adenosine deaminase acting on RNA 1 (ADAR1) in macrophages (P＜0.01), and an increase in the expression of Z-DNA binding protein 1 (ZBP1), phosphorylated receptor-interacting serine/threonine-protein kinase (p-RIPK3), and phosphorylated mixed lineage kinase domain-like protein (p-MLKL) (all P＜0.01). Compared with the control group, the plasma lipid levels of ApoE－/－ mice in the hypobaric hypoxia group did not change significantly (P＞0.05), the plasma inflammatory cytokines (TNF-α, IL-1β, IL-6 and MCP-1) increased (all P＜0.05), the area of atherosclerotic plaque increased (P＜0.05), the area of plaque necrotic core increased, the content of plaque collagen decreased, the number of macrophages increased, the expression of ADAR1 decreased, and the expression of ZBP1 and p-MLKL increased (all P＜0.01). Conclusion Hypobaric hypoxia causes the imbalance of ADAR1/ZBP1 expression in macrophages, activates RIPK3/MLKL signaling pathway, promotes macrophage necroptosis, increases the area of plaque necrosis core, and leads to increase instability of atherosclerotic plaque.