Abnormal extracellular microenvironment signals of macrophages contribute to the occurrence and progression of metabolic diseases. Macrophage metabolism is a therapeutic target for treating metabolic diseases. However, molecular mechanisms of metabolic disturbances in the extracellular microenvironment of macrophages remain unclear. Here, an untargeted metabolomics approach based on gas chromatography–mass spectrometry revealed significant metabolic disturbances in the extracellular microenvironment of oleate-treated macrophages. Most of above changes were responsive to resveratrol and/or pioglitazone intervention. Notably, the concentration levels of most saccharides and lactate were increased in the extracellular microenvironment of the oleate-treated macrophages. The increased levels of fructose and lactate were abolished by resveratrol and/or pioglitazone treatment. Additionally, the concentrations of isoleucine and metabolites derived from branched-chain amino acids (including 4-methyl-2-oxovalerate, 3-methyl-2-oxobutanoate, and 3-methyl-2-oxovalerate) were increased in the extracellular microenvironment of the oleate-treated macrophages. These effects were alleviated or abolished by both resveratrol and pioglitazone treatments. Moreover, myristate and oleate accumulated in the extracellular microenvironment of the oleate-treated macrophages. The metabolic disturbances in the extracellular microenvironment of oleate-treated macrophages indicated carbohydrate metabolism, glycolysis, branched-chain amino acid metabolism and fatty acid metabolism as potential therapeutic targets for treating metabolic diseases and the intervention effects of resveratrol and pioglitazone. To the best of our knowledge, this study is the first to demonstrate the accumulation of saccharides, lactate, isoleucine and branched-chain amino acid-derived metabolites in the extracellular microenvironment of macrophages.