The occurrence of clear cell renal cell carcinoma (ccRCC) is related to changes in the transforming growth factor-β (TGF-β) signaling pathway. In this study, we adopted an integrated approach to identify and verify the effects of changes in this pathway on ccRCC and provide a guide for identifying new therapeutic targets. We performed transcriptome analysis of 539 ccRCC cases from The Cancer Genome Atlas (TCGA) and divided the samples into different TGF-β clusters according to unsupervised hierarchical clustering. We found that 76 of the 85 TGF-β pathway genes were dysregulated, and 55 genes were either protective or risk factors affecting the prognosis of ccRCC. The survival time of patients with tumors with low TGF-β scores was shorter than that of patients with tumors with high TGF-β scores. The overall survival (OS) of patients with ccRCC with high TGF-β scores was better than that of patients with low TGF-β scores. The TGF-β score correlated with the expression of key ccRCC and deacetylation genes. The sensitivity of tumor patients to targeted drugs differed between the high and low TGF-β score groups. Therefore, a prognostic model based on the TGF-β gene pathway can predict the prognosis of ccRCC patients. Grouping patients with ccRCC according to their TGF-β score is of great significance for evaluating the prognosis of patients, selecting targeted drugs, and identifying new therapeutic targets.