<p>Atherosclerosis (AS) remains the main cause of vascular diseases. This study reveals the effects of safranal and underlying mechanisms in RAW264.7 macrophages under AS context, which is hoped to facilitate its clinical application. Safranal reduced AS progression in ApoE (−/−) mice, and it also increased the serum level of HDL-C and decreased the levels of TG, TC, and LDL-C as well as ALT and AST. Besides, safranal repressed the pathophysiological processes of OS (downregulated levels of ROS and MDA and upregulated biosynthesis of GSH), ERS (decreased protein levels of activating transcription factor 6, X-Box Binding Protein 1, and glucose-regulated protein, 78&#xa0;kDa), and inflammation (downregulated serum levels of TNF-α, IL-1β, and IL-6) in vivo. Mechanistically, safranal repressed PI3K/Akt and NF-κB signaling pathways in vivo. On the cellular level, safranal treatment relieved the uptake of ox-LDL, and decreased contents of TG, TC, and LDL-C while increasing HDL-C level in ox-LDL-treated RAW264.7 macrophages. It also reduced the molecular indexes of pathophysiological processes (OS, ESR, and release of inflammatory mediators) in ox-LDL-exposed RAW264.7 macrophages. Notably, safranal treatment also impaired PI3K/Akt and NF-κB signaling pathways in ox-LDL-exposed RAW264.7 macrophages. Additionally, the PI3K agonist 740Y-P notably reversed the in vitro inhibitory effects of safranal on lipid deposition, productions of TC and TNF-α, and protein levels of molecules of PI3K/Akt and NF-κB signaling pathways. Safranal exerts anti-AS effects via repressing OS, ERS, and inflammation in ApoE (−/−) mice, and it also negatively modulates PI3K/Akt and NF-κB signaling pathways in RAW264.7 macrophages. </p> Graphical abstract <p>Safranal reduces oxidative stress, endoplasmic reticulum stress, and release of inflammatory factors to relieve atherosclerosis progress partly via repressing PI3K/Akt and NF-κb pathways in RAW264.7 macrophages.</p> <p></p>