Sulforaphane (SFN), an isothiocyanate, is one of the major dietary phytochemicals found in cruciferous vegetables. Many studies suggest that SFN can protect against cancer and cardiometabolic diseases. Despite the proposed systemic and local vascular protective mechanisms, SFN’s potential to inhibit atherogenesis by targeting macrophages remains unknown. In this study, in high fat diet fed ApoE-deficient (ApoE−/−) mice, oral SFN treatment improved dyslipidemia and inhibited atherosclerotic plaque formation and the unstable phenotype, as demonstrated by reductions in the lesion areas in both the aortic sinus and whole aorta, percentages of necrotic cores, vascular macrophage infiltration and reactive oxygen species (ROS) generation. In THP-1-derived macrophages, preadministration SFN alleviated oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation, oxidative stress and mitochondrial injury. Moreover, a functional study revealed that peritoneal macrophages isolated from SFN-treated mice exhibited attenuated cholesterol influx and enhanced apolipoprotein A-I (apoA-I)- and high-density lipoprotein (HDL)-mediated cholesterol efflux. Mechanistic analysis revealed that SFN supplementation induced both intralesional and intraperitoneal macrophage phenotypic switching toward high expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and ATP-binding cassette subfamily A/G member 1 (ABCA1/G1) and low expression of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36), which was further validated by the aortic protein expression. These results suggest that the regulation of macrophages’ cholesterol transport and accumulation may be mainly responsible for SFN’s potential atheroprotective properties, and the regulatory mechanisms might involve upregulating ABCA1/G1 and downregulating CD36 via the modulation of PPARγ and Nrf2.