As the primary receptor of oxidized low-density lipoprotein (ox-LDL), LOX-1 is a putative therapeutic target for atherosclerotic disorders including ischemic stroke (IS), whereas the regulatory mechanism of LOX-1 remains largely unknown in IS. We employed computational algorithms to screen candidate miRNAs, followed by integrative analysis of differentially expressed miRNA profiles derived from blood cells of 25 acute IS cases and 25 controls matched with age and gender. MiR-187-3p-mediated regulation of LOX-1 was confirmed by a dual-luciferase reporter assay and Western Blot in THP-1 derived macrophages. Elevated blood levels of miR-187-3p were observed both in IS patients and the atherosclerotic mice. In a case-control study enrolling 279 IS cases and 279 controls, we found that miR-187-3p level was significantly associated with the occurrence of IS (adjusted OR = 1.204; 95% CI: 1.086-1.335; p < 0.001). Similar results were replicated in another coronary heart disease case-control population. In vivo, systemic delivery of agomiR-187-3p significantly reduced atherosclerotic plaque burden alongside decreased plasma lipids and suppressed inflammation. In vitro, miR-187-3p over-expression attenuated foam cell formation induced by ox-LDL and down-regulated pro-inflammatory mediators in macrophages. Conversely, miR-187-3p inhibition exacerbated these effects, which were partially rescued by LOX-1 inhibitor BI-0115. This study establishes miR-187-3p as a novel epigenetic regulator of LOX-1 and provides critical evidence supporting its therapeutic potential for modulating IS progression.