Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. An important intrinsic cause of renal fibrosis is epigenetic alterations. SET domain containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalyzing H3K36 dimethylation to trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. Clinical data indicate that SETD2 is lowly expressed in patients with renal fibrosis. Here, we established genetically engineered mice with SETD2 and VHL deficiency. SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the TGF-β/Smad signaling pathway, thereby preventing the activation of the TGF-β/Smad signaling pathway. Deletion of SETD2 leads to reduced smad7 expression, which results in activation of the TGF-β/Smad signaling pathway and ultimately fibrosis in the absence of VHL. Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-β/Smad signaling pathway in renal fibrogenesis. Thus, our study provides innovative insights into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.