Calpains (CAPNs) are intracellular calcium-activated neutral cysteine proteinases involved in cancer initiation, progression, and metastasis. However, its role in pancreatic cancer (PC) is still unclear. This study aims to identify the prognostic value and immune infiltration of CAPNs for PC patients using comprehensive bioinformatics analyzes. We analyzed the transcription levels of CAPNs in different cancers from Oncomine, differential gene expression in tumor/normal tissues and pathological stage through GEPIA database, the prognostic value of the mRNA expression of CAPNs by Kaplan-Meier plotter, the protein expression comparison of different CAPNs in human tumor/normal tissues from The Human Protein Atla, the CAPNs gene alterations through cBioPortal, the prediction of protein-protein interactions by STRING and GeneMANIA, the functional enrichment of discrepant CAPNs by GO and KEGG, and the immune infiltration of CAPNs by ssGSEA. Our results showed that CAPN1, 2, 4, 5, 6, 8, 9, 10, and 12 were highly expressed in PC. CAPN1, 5, 8, and 12 expression levels were positively correlated with individual cancer stages. Furthermore, CAPN1, 2, 5, and 8 expression levels were negatively correlated with overall survival (OS) and recurrence-free survival (RFS), while CAPN10 was positively correlated with OS and RFS. We found that CAPN1, 2, 5, and 8 were correlated with tumor-infiltrating T follicular helper cells and CAPN10 with tumor-infiltrating T helper 2 cells. Functional enrichment analysis showed that differentially expressed CAPNs (CAPN1, 2, 5, 8, and 10) are involved in axonogenesis, cell-substrate adhesion, immune response-activating cell surface receptor signaling pathway, and cell junction organization in PC. These results suggested that CAPN1, 2, 5, 8, and 10 could be used as prognostic biomarkers in PC and improve individualized treatment strategies.