Integrin β3 (ITGB3) acts as a crucial regulator and target within the tumor immune microenvironment (TIME) and is highly expressed in the TIME of various tumors. The TIMER, TCGA, GTEx, and CCLE databases were utilized to comprehensively analyze the differential expression of ITGB3 in tumor tissues. Kaplan–Meier analysis, forest plots, and univariate and multivariate Cox regression were used to assess the genetic alterations, clinicopathological characteristics, and prognostic value of ITGB3. Additionally, the R software package was used to evaluate the relationship between ITGB3 expression and immune cell infiltration, immunomodulatory genes, and immune checkpoints, and potential signaling pathways were examined through differential expression and enrichment analysis. We found that the high expression of ITGB3 is a significant risk factor for six types of cancer, including adrenocortical carcinoma (ACC), and is closely associated with a lower survival rate. Anti-tumor immune cells (CD8 + T cells, CD4 + Th1 cells, and NKT cells) were significantly reduced. By contrast, pro-tumor immune cells (Tregs and CD4 + Th2 cells), immune checkpoints (CTLA4 and PD-CD1), and negatively regulated co-stimulators of T-cell activation (CTLA4, PD-CD1, and IL10) were significantly elevated in most types of cancer with high ITGB3 expression. Overall, our preliminary results indicate that ITGB3 plays an important role in immunosuppression in the tumor microenvironment. Elevated levels of ITGB3 inhibit tumor immunity, facilitate tumor immune escape, and affect patient prognosis, and it may be a prognostic biomarker.