Obesity and related metabolic disorders are worldwide epidemics. Current lifestyle interventions and drug treatment for obesity seem insufficient. Here, we show that Loureirin B (LB), a major flavonoid molecule extracted from Sanguis Draxonis, prevents diet-induced obesity and ameliorates concomitant metabolic abnormalities including fatty liver, insulin resistance and systemic inflammation in mice. Mechanistically, LB treatment increases the proportion of ω3 polyunsaturated fatty acids (PUFAs) in brown adipose tissue (BAT) and white adipose tissue (WAT), which subsequently activates the key lipid sensor GPR120. In line with this, LB treatment promotes browning of WAT and activates BAT thermogenesis through upregulation of UCP1, a downstream effector of GPR120. Conversely, inhibition of GPR120 abolishes the thermogenic effect of LB in primary cultured brown adipocytes. Together, these results suggest that LB possesses anti-obesity property by enhancing adipose tissue thermogenesis via activation of ω3 PUFA-GPR120-UCP1 axis and holds promises for combating obesity and its related metabolic syndrome.