Atherosclerosis is a chronic inflammatory process, plaque rupture and subsequent thrombosis underline the major causes of acute cardio-cerebral vascular diseases. Long non-coding RNAs (lncRNAs) participate in diverse pathologic processes, including inflammation and myocardial infarction. Recent study confirmed the elevation of lncRNA growth arrest-specific 5 (GAS5) in atherosclerotic rats. In this study, we aimed to explore the role and mechanism of GAS5 in the progression of atherosclerotic plaque. Here, expression of GAS5 was enriched in atherosclerotic plaques and THP-1 macrophage exposed to oxidized low-density lipoprotein (ox-LDL). Furthermore, overexpression of GAS5 aggravated ox-LDL-induced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and chemokine MCP-1 secretion in macrophages, which were reversed after GAS5 cessation. Additionally, high expression and secretion of MMP-2 and MMP-9 were increased in ox-LDL-stimulated macrophages following GAS5 elevation, but these increases were inhibited in GAS5-silenced group. Mechanism analysis identified GAS5 as a endogenous sponge to directly bind and suppress miR-221 expression. Notably, miR-221 elevation antagonized GAS5-enhanced inflammatory response and MMPs in macrophages upon ox-LDL. These results suggest that GAS5 can trigger inflammatory response and MMP expression by acting as a sponge of miR-221, which may facilitate fibrous cap degradation and aggravate atherosclerotic plaque destabilization, supporting a promising therapeutic agent against atherosclerosis.