The endocrine and exocrine compartments of the pancreas are spatially related but functionally distinct. Multiple diseases affect both compartments, including type 1 diabetes (T1D), pancreatitis, cystic fibrosis, and pancreatic cancer. To better understand how the exocrine pancreas changes with age, obesity, and diabetes, we performed systematic analysis of wellpreserved tissue sections from the pancreatic head, body, and tail of organ donors with T1D (n = 20), type 2 diabetes (T2D, n = 25), and donors with no diabetes (ND, n = 74). Among ND donors, we found that acinar-to-ductal metaplasia (ADM), angiopathy, and pancreatic adiposity increased with age, while ADM and adiposity also increased with BMI. Compared to age- and sex-matched ND organs, T1D pancreata had greater acinar atrophy and angiopathy with fewer intralobular adipocytes. T2D pancreata had greater ADM, angiopathy, and total T lymphocytes, but no difference in adipocyte number, compared to ND organs. While total pancreatic fibrosis was increased in both T1D and T2D, the pattern was different with T1D pancreata having greater periductal and perivascular fibrosis, whereas T2D pancreata had greater lobular and parenchymal fibrosis. Thus, the exocrine pancreas undergoes distinct changes as individuals age or develop T1D or T2D.