Metastasis　remains　the　leading　cause　of　death　from　lung　carcinoma.　It　is　urgent　to　find　safe　and　efficient　pre-metastasis　preventive　agents　for　cancer　survivors.　We　isolated　a　flavonoid　glycoside,　hexamethoxy　flavanone-o-[rhamnopyranosyl-(1 → 4)-rhamnopyranoside　(HMFRR),　from　the　traditional　Chinese　medicine　(TCM)　Murraya　paniculata　(L.)　that　can　effectively　inhibit　the　adhesion,　migration,　and　invasion　of　lung　adenocarcinoma　A549　cells　in　vitro.　Molecular　and　cellular　studies　demonstrated　that　HMFRR　significantly　downregulated　the　expressions　of　cell　adhesion-related　and　invasion-related　molecules　such　as　integrin　β1,　EGFR,　COX-2,　MMP-2,　and　MMP-9　proteins.　Additionally,　HMFRR　effectively　downregulated　the　expressions　of　epithelial–mesenchymal　transition　(EMT)　markers　(N-cadherin　and　vimentin)　and　upregulated　that　of　E-cadherin.　Moreover,　these　inhibitions　were　mediated　by　interrupting　STAT3/NF-κB/COX-2　and　EGFR/PI3K/AKT　signaling　pathways.　Furthermore,　HMFRR　counteracted　the　expressions　of　cell　adhesion　molecules　(ICAM-1,　VCAM-1,　and　E-selectin)　stimulated　by　interleukin-1β　in　human　pulmonary　microvascular　endothelial　cells　(HPMECs).　As　a　result,　HMFRR　interrupted　the　adhesion　of　A549　cells　to　HPMECs.　Collectively,　these　results　indicate　that　HMFRR　may　become　a　good　candidate　for　cancer　metastatic　chemopreventive　agents　by　interrupting　the　STAT3/NF-κB/COX-2　and　EGFR　signaling　pathways.　©　2017,　American　Association　of　Pharmaceutical　Scientists.