Paxillin (PXN) is a protein involved in numerous physiological processes, and its presence is closely related to the occurrence and development of many types of tumors. However, no studies have analyzed PXN from a pan-cancer perspective. We analyzed PXN expression, immune cell infiltration, prognosis, and biological function across different types of tumors included in The Cancer Genome Atlas and Gene Expression Omnibus datasets. The results showed that expression of PXN varies in different tumors. Expression of PXN strongly correlated with prognosis in patients with tumors; higher PXN expression usually was linked to poor overall and disease-free survival. Expression of PXN in breast invasive carcinoma and lymphoid neoplasm diffuse large B-cell lymphoma was related to the degree of CD8+ T-cell infiltration, and infiltration of cancer-associated fibroblasts, such as kidney renal papillary cell carcinoma and brain lower-grade glioma, was also observed in other tumors. The results of pan-cancer analysis showed that abnormal PXN expression was related to poor prognosis, immune infiltration, and protein phosphorylation in different tumor types. Therefore, the PXN gene may become a potential biomarker of clinical tumor prognosis.