Clear cell renal cell carcinoma (ccRCC) was the most aggressive histological type of renal cell carcinoma (RCC) and accounted for 70-80% of cases of all RCC. The aim of this study was to identify the potential biomarker in ccRCC and explore their underlying mechanisms. Four profile datasets were downloaded from the GEO database to identify DEGs. GO and KEGG analysis of DEGs were performed by DAVID. A protein-protein interaction (PPI) network was constructed to predict hub genes. The hub gene expression within ccRCC across multiple datasets and the overall survival analysis were investigated utilizing the Oncomine Platform and UALCAN dataset, separately. A meta-analysis was performed to explore the relationship between the hub genes: EGFR and ccRCC. 127 DEGs (55 upregulated genes and 72 downregulated genes) were identified from four profile datasets. Integrating the result from PPI network, Oncomine Platform, and survival analysis, EGFR, FLT1, and EDN1 were screened as key factors in the prognosis of ccRCC. GO and KEGG analysis revealed that 127 DEGs were mainly enriched in 21 terms and 4 pathways. The meta-analysis showed that there was a significant difference of EGFR expression between ccRCC tissues and normal tissues, and the expression of EGFR in patients with metastasis was higher. This study identified 3 importance genes (EGFR, FLT1, and EDN1) in ccRCC, and EGFR may be a potential prognostic biomarker and novel therapeutic target for ccRCC, especially patients with metastasis.