<p>Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile toward a synthetic phenotype plays a critical role in atherosclerosis. Although the redox-sensitive sentrin/Small Ubiquitin-like Modifier (SUMO)-specific protease 3 (SENP3), which preferentially deconjugates SUMO2/3, has been linked to oxidative stress, its role in atherosclerosis remains poorly defined. In this study, we demonstrate that SENP3 is significantly upregulated in human and mouse atherosclerotic lesions and in VSMCs exposed to pro-atherogenic stimuli. Using smooth muscle-specific <i>Senp3</i> knockout mice (<i>ApoE</i>^−/−;<i>Senp3</i>^{<i>flox/flox</i>};<i>Tagln-Cre)</i> and SENP3-knockdown VSMC models, we show that SENP3 deficiency preserves the contractile phenotype of VSMCs, suppresses their proliferation and migration, and attenuates atherosclerotic lesion development. Specifically, <i>Senp3</i> deletion reduces plaque formation and lipid accumulation, while enhancing collagen deposition and fibrous cap stability, shifting plaques toward a more stable phenotype. Mechanistically, we determined the transcription factor Krüppel-like factor 4 (KLF4) as a direct substrate of SENP3. SENP3 deSUMOylates KLF4 at lysine 278, thereby inhibiting its ubiquitin-mediated degradation and increasing its stability. We further show that SUMOylation at K278 serves as an intrinsic brake on KLF4-mediated phenotypic switching in VSMCs. These findings reveal that SENP3‐driven deSUMOylation of KLF4 regulates VSMC phenotypic switching in atherosclerosis, highlighting the SENP3/KLF4 axis as a pivotal regulator of vascular plasticity and a promising therapeutic target for atherosclerotic disease.</p>