Macrophages participate in plaque formation and development through the process of foam cell formation, and mitochondria play a crucial role in macrophage phenotype transformation. However, the mitochondrial metabolic characteristics of macrophages during foam cell formation have not been systematically studied. In this work, we investigated the mechanism of mitochondrial metabolic reprogramming during macrophage foam cell formation using proteomics, metabolomics and lipidomics. Multi-omics integrative analysis highlighted key metabolic pathway changes, including the tricarboxylic acid cycle fragmentation, and the recombination of mitochondria protein complexes and mitochondria membrane lipids.