Insulin resistance is a key pathological process in the development of type II diabetes, which can also lead to depression, anxiety and other symptoms. With the accelerated pace of life, food with high-energy and additives is becoming more and more common in people's diet. Propionate is a naturally existing short-chain fatty acid salt that has been widely used as a food preservative, but studies have found that low concentrations of propionate can induce insulin resistance. Theaflavins (TFs) are characteristic components of black tea, which have the biological activity of hypoglycemic and lipid-lowering. In the present study, we used propionate combined with high-fat diet to induce insulin resistance in mice and treated them with theaflavins. The results showed that propionate could aggravate insulin resistance and anxiety induced by high-fat diet in mice. TFs alleviated insulin resistance and anxiety induced by propionate combined with high-fat diet by improving the disorder of metabolic gene expression and inflammation in the adipose and liver tissue, as well as neuroinflammation in the brain. Our study suggests that the food additive propionate combined with a high-fat diet may be harmful to organismal health. As a natural drug, TFs have the potential to alleviate insulin resistance induced by propionate combined with high-fat diet.