Background <p>Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, with its incidence increasing annually. This study aims to investigate the role of the Cyclin-Dependent Kinase Inhibitor 2&#xa0;A (CDKN2A) in ccRCC.</p> Methods <p>We analyzed ccRCC-related data from the TCGA and GEO databases. First, we systematically assessed the expression levels of CDKN2A and its correlation with clinical features, such as tumor staging and prognosis. Additionally, regarding biological function, we explored the relationship between CDKN2A expression and immune cell infiltration, along with the mechanisms underlying this relationship. We also examined the association between CDKN2A and drug sensitivity through drug sensitivity analysis. Furthermore, we experimentally validated the differential expression of CDKN2A in ccRCC and its impact on the cellular behaviors of ccRCC cells.</p> Results <p>The results revealed that CDKN2A expression was significantly higher in ccRCC tissues compared to normal kidney tissues, affecting patient prognosis by modulating the tumor microenvironment. Moreover, based on data from the GDSC, and CTRP databases, we found that high CDKN2A expression was closely associated with sensitivity to certain small-molecule drugs. These drugs particularly target the MAPK pathway. Experimental findings indicated that CDKN2A promotes the proliferation, migration, and invasion of ccRCC cells via the MAPK pathway.</p> Conclusions <p>Our study suggests that CDKN2A has an oncogenic role in ccRCC and may serve as a potential therapeutic target.</p>