Clear cell renal cell carcinoma (ccRCC) is a malignant tumor with dysregulated lipid metabolism, and is highly incidental in polycystic kidney disease (PKD) patients. However, SETD2 is an important tumor suppressor gene in ccRCC generation, yet the underlying mechanisms, especially the effects of lipid metabolism, remain largely unexplored. Here, we revealed extensive and large-scale metabolic reprogramming events in a SETD2-deficient ccRCC mouse model by performing a multi-omics study comprising transcriptomics, proteomics, metabolomics, lipidomics and metabolic mass spectrometry imaging approaches. Our data unveiled dramatic alteration of fatty acid biosynthesis, glycerolipid metabolism, glycerophospholipid metabolism, tricarboxylic acid cycle (TCA), carbohydrate digestion and absorption, protein digestion and absorption and biosynthesis of amino acids, which eventually led to dysregulated sphingomyelin metabolism-related metabolic pathways. Clinically, we discovered that TCA and amino acid metabolism are positively associated with SETD2, while glycolysis, protein catabolic and lipids biosynthesis are negatively associated with SETD2. Mass spectrometry imaging of clinical ccRCC tissues revealed that SETD2 mutation is associated with upregulated sphingomyelin biosynthesis in human ccRCC. Our study provides a comprehensive resource of biological data to support future investigations of SETD2-deficient ccRCC, facilitating the development of metabolically targeted therapeutic modalities.