Abnormal thyroid hormone (TH) function has been observed in all components of metabolic syndrome (MetS), but the mechanisms remain unclear. Altered genomic methylation status is closely related to MetS. Our aim was to determine whether methylation regulation in TH function–related genes is involved in MetS. In a small strictly selected cohort, low TH function was observed in MetS group, as well as lower
THRB
promoter methylation levels in peripheral blood leukocytes in a genome-wide methylation screening by Illumina 450K beadchip. The results of beadchip assay were then confirmed by Sequenom MassARRAY. Low
THRB
promoter methylation levels and low TH function in MetS were confirmed in another big-size validation cohort. Lower methylation levels were associated with higher
THRB
expression in peripheral blood leukocytes, and altered
THRB
promoter methylation status influenced its promoter activity and expression. In the MetS rat models constructed by high fat and high fructose diet, lower TH function was also observed, as well as lower
Thrb
promoter methylation levels. Furthermore, systematic inflammation observed in MetS was found to induce decreased
THRB
promoter methylation levels as well as corresponding
THRB
expression. Additionally, oral treatment with a physiological T3 dose mitigated hypertension and insulin resistance and partially alleviated hepatic steatosis and adipocyte hypertrophy in MetS rats. Low methylation levels of
THRB
promoter in peripheral blood leukocytes induced by systematic inflammation were involved in low TH function in MetS, whereas low TH function deteriorates MetS. This might serve as a novel therapeutic target of MetS.