Introduction: Oxidative stress induced vascular remodeling promotes atherosclerosis. By scavenging excessive ROS levels, NRF2 protects vascular cells against oxidative stress and exerts anti-inflammatory activity through modulation of HO-1. This study aimed to explore smooth muscle cell (SMC)-specific role of SMYD2 in modulating atherosclerosis associated oxidative stress in vivo and in vitro . Methods: SMC-specific SMYD2 knockout mice in ApoE -/- background (SMYD2 ΔSMC ApoE -/- ) and their littermate controls (SMYD2 fl/fl ApoE -/- ) were subjected to Western diet feeding for 18-26 weeks. Atherosclerotic plaque distribution was examined by en-face Oil Red O (ORO) staining of aortas from both groups. Hematoxylin & Eosin (H&E) staining on brachiocephalic artery tissues were performed to determine atherosclerotic plaque burden by measurements of total plaque size, lipid pool area, and necrotic core area. Lipid peroxidation was analyzed in aortic tissues and in blood serum. Primary VSMCs isolated from control and SMYD2 depleted mice and cultured C3H/ 10T1 / 2 cells were used for in vitro studies. Results: SMC-specific SMYD2 depletion attenuated atherosclerotic plaque establishment and progression. En -face ORO analysis revealed significant suppression of ORO positive areas in SMYD2 ΔSMC ApoE -/- mice compared to control mice. H&E analysis of lesions showed significant reduction of total plaque size, despite accumulation of lipids, in SMYD2 ΔSMC ApoE -/- mice as compared to control mice. Immunofluorescence staining of aortic tissues showed increased expression of NRF2, HO-1 and GPX4 in SMYD2 ΔSMC ApoE -/- mice compared to controls, as observed in serum by MDA assay. Mechanistic studies using C3H/ 10T1 / 2 cells treated with PAz-PC (oxLDL), GPX4 inhibitor, with or without SMYD2 knockout, demonstrated that SMYD2 modulates HO-1 and GPX4 expression through NRF2. Specifically, SMYD2 binds NRF2 and reduces its translocation into the nucleus, thereby repressing HO-1 expression and inducing oxidative stress. Conclusion: SMYD2 depletion induces atheroprotective effect via reducing plaque burden and promoting antioxidant activity of NRF2/HO-1 axis, suggesting SMYD2 could be a therapeutic target against atherosclerosis.