Circulating palmitic acid (PA) is generally considered to be provided from diets and endogenous synthesis and is adversely correlated with cardiovascular disease (CVD). It is unknown, however, if gut microbiota modulates circulating PA and potentiates CVD risk. Here we demonstrate that, in CVD patients, elevated circulating PA is accompanied with hypercoagulability and high gut Bacteroides thetaiotaomicron (BT) abundance. PA promotes coagulation by inhibiting a major endogenous anticoagulant activated protein C (APC) and enhancing platelet activation. Importantly, BT is capable of synthesizing PA, and high-fat diet amplifies gut BT colonization. Our findings show that BT transplantation elevates plasma PA and triggers hypercoagulation without alternating host lipogenesis. Hesperidin, adietary flavonoid, inhibits PA-APC interaction to prevent hypercoagulation induced by PA or BT transplantation. Collectively, we reveal the promotion of high-fat diet on gut BT colonization that elevates circulating PA and CVD risk, suggesting an approach controlling CVD by targeting PA and BT.