<p>This study aimed to explore the role of lactoferrin (LTF) in atherosclerosis (AS) and its possible mechanisms. Human left coronary artery tissues were collected and divided into control (CON), coronary heart disease (CHD) and sudden coronary death (SCD) groups. Pathologic changes (including changes in the coronary plaque area, necrotic core, collagen fibers, and foam cell content) were observed. The LTF, P62, and 4-hydroxynonenal (4-HNE) expression levels were assessed. The <i>ApoE</i>^{<i>–</i>/<i>–</i>} AS mouse model was established. The pathological changes and related protein levels were analyzed after autophagy inhibition. The foam cell model was constructed using an ox-LDL-induced human monocyte line, THP-1. The LTF, BECN1, LC3-II/I, AMP-activated protein kinase (AMPK)/the mammalian target of rapamycin (mTOR) pathway proteins, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and 4-HNE expressions were then detected after silencing of LTF or BECN1. Plaque stability was significantly lower in the SCD group compared to the non-SCD group (<Emphasis Type="BoldItalic">p</Emphasis> <b>&lt; 0.05</b>). LTF, P62 and 4-HNE levels in plaques increased as plaque stability decreased, and LTF was significantly correlated with plaque progression and autophagy levels. Autophagy inhibition by U0126 leads to the worsening of aortic luminal stenosis, increased necrotic core and foam cell deposits, decreased autophagosomes, reduced LTF expression, and upregulated P62 expression in AS mice. It was further demonstrated that LTF expression correlates with autophagy. LTF expression was increased in ox-LDL-treated THP-1 cells, and silencing BECN1 and/or LTF increased mTOR phosphorylation and 4-HNE levels, inhibited BECN1 and LC3 II expression and AMPK activation, and simultaneously decreased the Bcl-2/Bax ratio. LTF might alleviate AS pathology through accelerating the AMPK/mTOR pathway, and suggested that LTF may be a potential predictive molecule for AS.</p>