Single-minded homolog 2 (SIM2) has been identified as a potential contributor to the development of solid tumors. Despite this, there is a lack of comprehensive research regarding its biological role and underlying mechanism within pancreatic cancer (PC), as well as its prognostic impact. This study systematically evaluated the expression level and clinical significance of SIM2 in patients with PC using various databases, including The Cancer Genome Atlas, KM Plotter, and gene expression profiling interactive analysis. To investigate the relationship between SIM2 expression and immune cell infiltration, we conducted ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) analyses. Single-minded homolog 2 was up-regulated in patients with PC. Pancreatic cancer patients with higher SIM2 expression had poorer overall survival rates. Gene set enrichment analysis results suggested that SIM2 may have a significant impact on the progression of PC and the regulation of immune responses. According to the ssGSEA algorithm, SIM2 has a negative correlation with the levels of infiltrating TFH, mast cells, and pDC. Our study demonstrated that SIM2 serves as a biomarker, and is associated with both prognosis and immune infiltration in PC. This provides a solid foundation for future investigations into the precise role of SIM2 in the carcinogenesis and progression of PC.