<p>Atherosclerosis is a chronic inflammatory disease that remains a leading cause of cardiovascular morbidity and mortality worldwide. While traditional risk factors such as hyperlipidemia, hypertension, and diabetes have been extensively studied, emerging evidence highlights the pivotal role of innate immune responses in disease progression. Among these, the interplay between macrophage-derived inflammasomes—particularly NOD-like receptor family pyrin domain containing 3 and absent in melanoma 2—and neutrophil extracellular traps has garnered increasing attention as a key inflammatory axis driving plaque development and instability. Activation of inflammasomes in macrophages promotes the maturation and secretion of pro-inflammatory cytokines, including interleukin-1 beta and interleukin-18, which contribute to foam cell formation, sustained vascular inflammation, and destabilization of the fibrous cap. Conversely, neutrophil extracellular traps released by activated neutrophils amplify inflammasome signaling in macrophages, creating a self-reinforcing inflammatory loop that exacerbates endothelial dysfunction and increases thrombotic risk. This bidirectional crosstalk not only accelerates the progression of atherosclerotic lesions but also enhances the likelihood of acute cardiovascular events such as myocardial infarction and stroke. Recent preclinical and clinical studies suggest that targeting this axis may offer novel therapeutic strategies. Pharmacological interventions—including small-molecule inflammasome inhibitors, interleukin-1 beta antagonists, peptidylarginine deiminase 4 inhibitors, and agents that degrade neutrophil extracellular traps—have shown potential in reducing vascular inflammation, stabilizing plaques, and preventing thrombosis. By integrating findings across molecular, cellular, and translational research, this review underscores the pathological significance of the inflammasome–neutrophil extracellular trap axis and highlights its promise as a therapeutic target in atherosclerosis. Further investigation into the regulatory mechanisms governing this interaction may lead to the development of more precise and effective interventions aimed at reducing the burden of cardiovascular disease.</p> Graphical Abstract <p></p>