This study examined the expression levels of OVO-like proteins (OVOLs) in clear cell renal cell carcinoma (ccRCC) tissues and their value in predicting disease prognosis. The transcript levels, genetic alterations, and biological functions of OVOLs and their correlation with tumor immune cell infiltration and drug sensitivity and survival outcomes, as well as their prognostic values, in patients with ccRCC were analyzed based on data obtained from The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, cBioPortal, and GSCALite databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed using R software (Bioconductor, clusterProfiler packages). A protein-protein interaction network was established and visualized using the R software with the ggplots package. The ggstatsplot package was used to plot the correlation between gene expression and immune cell infiltration. The mRNA expression levels of and were significantly downregulated in patients with ccRCC, whereas those of were upregulated. expression was correlated with tumor stage and histological grades. The , and levels were significantly correlated with the prognosis of patients with ccRCC, the infiltration of immune cells, and drug sensitivity. Multivariate and univariate analyses showed that the expression of was an independent prognostic factor for the overall survival (OS) of patients with ccRCC. The OVOL proteins were associated with various pathways, including tight junction, cell adhesion molecules, and ether lipid metabolism. Additionally, upregulation, and and downregulation in clinical ccRCC samples were experimentally verified. Thus, OVOL1 and OVOL2 are potential therapeutic targets and prognostic markers for ccRCC. Additionally, OVOL1 can serve as an independent prognostic factor for OS in patients with ccRCC.