More than half of Crohn's disease patients eventually develop intestinal strictures. Intestinal fibrosis is the excessive deposition of the extracellular matrix that obstructs intestinal movement. There is no approved medication to treat intestinal stricture. The roles of serum exosomal miRNAs in intestinal fibrosis are unknown. Serum exosomal miRNA sequencing was performed on samples of healthy donors and stricturing CD (CDS) patients. CDS patient-derived primary intestinal fibroblasts (CD-HIFs), CDS patient-derived serum exosomes (CDSE), human peripheral blood mononuclear cells (PBMCs), human colonic tissues, and mouse models of intestinal fibrosis were used. CDS patients had significantly lower serum exosomal miR205-5p levels than non-CDS patients and healthy donors. CDS patients had reduced miR205-5p expression in PBMCs. miR205-5p reduced its target Zinc finger E-box-binding homeobox 1 (ZEB1) and collagen protein expression in CDSE-treated CD-HIFs. In mouse models of intestinal fibrosis, overexpression of miR205-5p inhibited intestinal fibrosis, which was overcome by Zeb1 overexpression. Elafin, a human anti-fibrogenic protein, induced miR205-5p in intestinal fibroblasts. Inhibition of miR205-5p reversed the anti-fibrogenic effects of elafin in mice. Low serum exosomal anti-fibrogenic miR205-5p levels were associated with intestinal strictures in CD patients. miR205-5p can mediate the anti-fibrogenic effect of elafin by inhibiting ZEB1 and collagen expression.