Wound healing, chronic fibrosis, and epithelial tumor progression share certain common hallmarks, including the coagulation cascade, inflammatory response, activation of mesenchymal stromal cells, and extracellular matrix (ECM) remodeling. Deregulation of these processes, resulting in chronic inflammation or aberrant accumulation of ECM components, such as fibrillar collagen or hyaluronic acid (HA), contributes to exacerbated scar formation and promotes tumorigenesis. Thus, defining underlying mechanisms governing these processes is vital to understanding disease progression. CD44 is a transmembrane cell-adhesion receptor that primarily binds to HA, the predominant glycosaminoglycan found in the ECM. Owing to it ubiquitous expression on nearly all neuroectodermal-derived cells, CD44 has been implicated in an array of fibrotic and inflammatory processes. Altered CD44 expression or signaling is detected in models of acute injury and epithelial tumors, but the role of CD44 in mediating cellular functionality and matrix remodeling in cutaneous wound healing and distinct epithelial tumors, such as pancreatic ductal adenocarcinoma (PDA), remains poorly understood. We demonstrated that in an excisional biopsy punch cutaneous wound healing model, CD44 mediated the kinetics of fibrotic and inflammatory responses with ultimate implications in scar formation. During injury resolution, CD44- null mice exhibited reduced collagen degradation leading to increased fibrillar collagen accumulation and exacerbated scar formation. These data indicate a previously unknown role of CD44 in regulating fibrillar collagen accumulation and wound healing in response to injury. In epithelial tumors, the cross-talk between neoplastic and nonneoplastic cells is a key determinant of tumor progression. CD44 is expressed in both neoplastic and non-neoplastic cellular compartments; however, its functionality during pancreatic tumorigenesis is poorly understood. Using autochthonous tumor models with tissue-specific CD44 deletion, we found a novel tumor-suppressive role of CD44 on neoplastic cells, by regulating neoplastic cell proliferation, and tumor-protective role of CD44 on non-neoplastic cells, by regulating fibrillar collagen accumulation. Together, these findings demonstrate previously unknown roles of CD44 in mediating underlying processes that fuel wound healing, fibrosis, and epithelial tumor progression.