Renal cell carcinoma is a cancer with a complex genetic background, and studies have shown that aberrant epigenetic regulation is one of the major causes of renal cell carcinogenesis. Histone methyltransferase SETD2 is an important epigenetic molecule and has a high mutation rate in renal cell carcinoma. To investigate the role and mechanism of SETD2 in the development of renal cell carcinoma, this study used a mouse model of kidney-specific knockout of SETD2 with renal cell carcinoma phenotype analysis, and found that deletion of SETD2 in VHL-deficient conditions could lead to renal cell carcinoma development. According to the transcriptome sequencing results, SETD2 knockdown led to the activation of Wnt/β-catenin and FoxO signaling pathways. This study provides new therapeutic targets and therapeutic ideas for the treatment of renal cell carcinoma.