Obesity-induced metabolic dysfunctions increase risk of vascular diseases including type II diabetes and stroke. While managing obesity is an interest to address the worldwide health problem, how genetic variability affects human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A single nucleotide polymorphism (SNP) in the brain derived neurotropic factor (BDNF) gene that results in the substitution of a valine to a methionine at codon 66 (val66met) occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of CD36, a multifunctional receptor implicated in obesity and insulin resistance, in wild-type mice and mice with the bdnf val66met variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese wild-type mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was aborted in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the val66met variant in both alleles (BDNFM/M) fed high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNFM/M mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extreme obese BDNFM/M mice compared to the wild-type mice. The study demonstrated a link between bdnf val66met and elevated CD36 expression, and suggested that CD36 inhibition may be a novel strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.