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In contrast to the stem and fruit of <i>Akebia quinata</i>, <i>A. quinata</i> leaves as a source rich in phenolic compounds with potentially beneficial pharmacological activities have been largely overlooked. To develop and use <i>A. quinata</i> leaves as a resource, we evaluated its potential as a cardiovascular-protective agent. Herein, we investigated the effects and potential mechanisms of <i>A. quinata</i> leaves extract on lipopolysaccharide (LPS)-induced inflammatory responses in human umbilical vein endothelial cells. We found that <i>A. quinata</i> leaves extract pretreatment of 10 μg/mL significantly attenuated LPS-induced protein expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1. Furthermore, this extract also suppressed LPS-induced phosphorylation of nuclear factor-κB p65. In order to elucidate the chemical profiles of the samples, the HPLC fingerprint was established, and prominent peaks were identified via HPLC–electrospray ionization–mass spectrometry. Multivariate statistical analyses, including hierarchical cluster analysis, principal component analysis, and partial least-squares discriminant analysis, were performed to evaluate the clustering of the samples. It was found that isochlorogenic acid C was a key marker for the classification of <i>A. quinata</i> leaves from the Gongju and Muju city in Korea. Collectively, this study not only suggested the potential of <i>A. quinata</i> leaves as a novel therapeutic candidate for inflammatory cardiovascular disease but also developed a quality control method for <i>A. quinata</i> leaves, which could help to expand the application of <i>A. quinata</i>.