Chronic pancreatic inflammation and pancreatic cancers arise within a profoundly altered stromal landscape that actively influences disease behavior. Increasing evidence suggests that the extracellular matrix (ECM) functions not merely as structural support but as a dynamic regulatory platform that modulates cellular signaling and tissue homeostasis. In both chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC), progressive changes in ECM composition and organization reshape the pancreatic microenvironment and influence disease progression and therapeutic response. This cell–ECM crosstalk regulates key biological processes such as proliferation, differentiation, migration, immune modulation, and survival. In the inflamed pancreas, persistent injury activates pancreatic stellate cells and immune populations, driving excessive deposition and remodeling of ECM components and promoting fibrosis and tissue stiffening. These alterations activate mechanosensitive signaling pathways, including integrin–FAK, TGF-β, YAP/TAZ, Hedgehog, and Wnt signaling, which collectively reinforce pathological inflammation and fibrogenesis. In PDAC, aberrant ECM remodeling further accelerates tumor progression by fostering epithelial–mesenchymal transition, immune evasion, metabolic adaptation, and resistance to chemotherapy, while simultaneously reprogramming the tumor microenvironment to sustain malignancy. Emerging evidence also highlights distinct roles for ECM dynamics in pancreatic neuroendocrine tumors and underscores the importance of biomechanical cues in disease evolution. This chapter summarizes current knowledge of molecular and mechanical mechanisms underlying cell–ECM interactions and discusses emerging therapeutic strategies targeting ECM remodeling in pancreatic diseases.