Pancreatitis, as a common exocrine pancreatic disease, poses a daunting challenge to patients’ health and the medical system. Endoplasmic reticulum stress (ERS) plays an essential role in the pathological process of pancreatitis. However, its mechanism is not fully understood. Therefore, this project was designed to deepen the understanding of the pathogenic mechanism of the disease by screening key ERS-related genes (hub genes) associated with pancreatitis. Through differential analysis and network analysis, we identified 4 hub genes (CCND1, BCL2, PIK3R1, and BCL2L1) from public databases. The receiver operation characteristic (ROC) curves indicated that they possessed good diagnostic capabilities. Subsequently, hub genes, especially BCL2 and PIK3R1, were elucidated to have strong interactions with 24 differentially expressed pancreatitis-related genes through differential analysis, Venn analysis, and correlation analysis. Further research revealed that these hub genes were closely linked to the immune microenvironment of pancreatitis, exhibiting negative correlations with Macrophages and Neutrophils, as well as a positive correlation with B_cells, CD8+_T_cells, and Tfh immune cells. Finally, we predicted potential miRNAs, lncRNAs, and compounds targeting these hub genes, providing reliable research directions for targeted studies on pancreatitis. In summary, this investigation not only further supports the function of ERS in pancreatitis development but also provides new perspectives and directions for the development of biomarkers for pancreatitis.