Objective: Endoplasmic reticulum (ER) stress is associated with alcoholic pancreatitis, but its role in pancreatic regeneration and the progression from acute pancreatitis (AP) to chronic pancreatitis (CP) remains unclear. This study investigates the influence of ER stress on pancreatic regeneration and its contribution to the progression from AP to CP. Design We explored the effects of ER stress on pancreatic regeneration and the AP-to-CP progression using alcohol exposure and the administration of ER stress inducer (tunicamycin), or inhibitors (4-PBAand TUDCA). We analyzed ER stress, inflammation, fibrosis, proliferation, and regeneration. Additionally, ER stress was studied in interleukin (IL)-10 knock out (KO) mice, and macrophages/neutrophils depleted models. the potential therapeutic effects of (-)-Catechin 7-O-b-D-xylopyranoside (CX) were also evaluated. Results: Chronic and binge alcohol consumption prolonged ER stress and unfolded protein responses (UPR) and delayed pancreatic regeneration compared to cerulein-induced pancreatitis. Distinct ER stress and UPR patterns were observed in M1 and M2 macrophages at early or late regenerative stage, with macrophages depletion delaying both ER stress resolution and regeneration. IL-10 KO mice showed persistent ER stress and impaired regeneration, indicating the role of IL-10 from M2-like macrophages in these processes. Sustained ER stress impaired pancreatic regeneration, contributing to AP-to-CP progression. Alcohol and tunicamycin or low dose cerulein (10 mg/kg) with tunicamycin induced pancreatitis, while ER stress inhibition prevented alcohol and ethyl palmitate-induced pancreatitis. We further discovered that CX administration reduced ER stress, enhanced regeneration, and prevented AP-to-CP progression. Conclusion: ER stress plays a key role in regulating pancreatic regeneration and contributes to the progression from AP to CP. Additionally, CX may offer therapeutic potential by modulating ER stress and enhancing pancreatic regeneration, suggesting a novel approach for pancreatitis