Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid HDAC3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon HDAC3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, HDAC3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify HDAC3 as a potential novel therapeutic target in cardiovascular disease. Synopsis: HDAC3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of HDAC3 is linked to plaque vulnerability to rupture. Myeloid HDAC3 deficiency promotes collagen deposition in atherosclerosis Macrophage HDAC3 deletion enhances TGF-β secretion thereby increasing collagen production by vascular smooth muscle cells and results in improved lipid handling by de-repression of PPARγ and LXR responses In humans, HDAC3 is upregulated in ruptured atherosclerotic lesions and is associated with inflammatory macrophages Fine-tuning of the macrophage phenotype by altering the epigenetic landscape can be applied to affect atherosclerotic disease outcome HDAC3 is shown to be an important modulator of the fibrotic phenotype of macrophages in atherosclerosis and, in humans, the expression of HDAC3 is linked to plaque vulnerability to rupture.