Excessive oxidative stress and decreased antioxidant capacity of macrophages are initial factors which cause macrophages to transform to foam cells, which represents a key event in the progression of atherosclerosis (AS). BML-111, the analog of lipoxin A (LXA) strongly attenuated high fat (HF) diet-induced atherosclerosis by activating NF-E2 related factor 2 (Nrf2). However, the effect was not through a specific LXA receptor (formyl peptide receptor 2, FPR2). BML-111 also strongly inhibited HF diet-induced promotion of MDA level, increased HDL level and decreased IL-1, MCP-1, IL-6, VCAM, ICAM and TNF-α level in aorta. In the in vitro experiments, LXA inhibited THP-1 cells to transform to foam cells via Nrf2 pathway. Our findings demonstrated that LXA and its analog prevented AS induced by HF diet in SD rats, under which the possible mechanism is through Keap1/Nrf2 pathway.