Abstract Atherosclerosis (AS) is a complex cardiovascular disease characterized by endothelial dysfunction, dyslipidemia, and immune‐inflammatory responses, leading to arterial plaque formation and potentially fatal complications such as myocardial infarction and stroke. Traditional treatments, such as statins, often pose challenges due to their side effects and limited efficacy. In this study, we explore a novel therapeutic approach utilizing engineered endothelial cells (ECs) targeting probiotic extracellular vesicles loaded with dihydrotanshinone I (DHT) (EC‐BEVs DHT ), a bioactive compound derived from Danshen ( Salvia miltiorrhiza Bunge). With the characterization of EC‐BEVs DHT by transmission electron microscope and nanoparticle tracking analysis, EC‐BEVs DHT exhibited typical spherical morphology and particle size distribution. High‐performance liquid chromatography coupled with tandem mass spectrometric confirmed the expression of the ECs‐targeting peptide VSSSTPR in EC‐BEVs DHT and EC‐BEVs DHT . We further investigated the anti‐atherosclerotic effects and molecular mechanisms of EC‐BEVs DHT on human umbilical vein endothelial cells (HUVECs) and Apolipoprotein E‐deficient (ApoE −/− ) C57BL/6J mice. We found that EC‐BEVs DHT attenuated oxidized low‐density lipoprotein induced HUVECs injury in vitro and decreased AS in ApoE −/− mice in vivo. Our findings suggest that EC‐BEVs DHT hold promise as a safe and effective therapeutic strategy for AS, offering potential advantages over traditional treatments.