The risk of inflammatory conditions caused by obesity is associated with an increased predisposition for additional pathological conditions, including cardiovascular risk factors. Adipose tissue stores energy and contributes to endocrine and immune functions that regulate homeostasis throughout the body. The effects of honokiol on vascular homeostasis in adipose tissue in high-fat diet (HFD)-induced obese mice are unclear. This study examined the protective effect of honokiol, an extract of traditional alkaloid herbs, on vascular endothelial cells in epididymal adipose tissue (EAT) and its regulatory effect on other metabolic parameters, such as the lipid droplet diameter, macrophage infiltration, and inflammation in HFDinduced obese mice. A HFD increased the density of platelet endothelial cell adhesion molecule-1 (PECAM-1)-1-positive vascular endothelial cells in EAT, which was decreased significantly by the honokiol treatment. Honokiol ameliorated the HFD-induced increase in lipid droplet diameter and increased macrophage infiltration in adipose tissue. Honokiol ameliorated the up-regulation of pro-inflammatory molecules and F4/80-positive macrophage infiltration in the adipose tissue of HFD-induced obese mice. Obese mice administered honokiol exhibited reduced mRNA expression of M1 macrophage (F4/80, TNF-, mIL-1, CD11c, and CCL2) and M2 macrophage (Arginase-1, FIZZ1, CD206, and TGF-1) markers in EAT. The vascular permeability was detected by Evans blue dye leakage in EAT of obese mice and treated mice with honokiol. These data suggest that honokiol regulates the angiogenic effects in adipose tissue and inflammation in HFDinduced obese mice.