Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr^−/−) mice were crossed with the Kras^G12D/+; Trp53^R172H/+; Ptf1a^Cre/+ (KPC) model of metastatic PDA. Ddr1^−/−; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1^−/−; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1^−/− mice were crossed with the Kras^G12D/+; Ptf1a^Cre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1^−/− models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1^−/− animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.