Salmonella enterica serovar Typhimurium is a clinically important gram-negative, enteric bacterial pathogen that activates several Toll-like receptors (TLRs). While TLR signaling through the adaptor protein MyD88 has been shown to promote inflammation and host defense against the systemic spread of S. Typhimurium, curiously, its role in the host response against S. Typhimurium within the mammalian gastrointestinal (GI) tract is less clear. We therefore used the recently described Salmonella-induced enterocolitis and fibrosis model: wild-type (WT) and MyD88-deficient (MyD88(-/-)) mice pretreated with streptomycin and then orally infected with the ΔaroA vaccine strain of S. Typhimurium. Tissues were analyzed for bacterial colonization, inflammation, and epithelial damage, while fibrosis was assessed by collagen quantification and Masson's trichrome staining. WT and MyD88(-/-) mice carried similar intestinal pathogen burdens to postinfection day 21. Infection of WT mice led to acute mucosal and submucosal inflammation and edema, as well as significant intestinal epithelial damage and proliferation, leading to widespread goblet cell depletion. Impressive collagen deposition in the WT intestine was also evident in the submucosa at postinfection days 7 and 21, with fibrotic regions rich in fibroblasts and collagen. While infected MyD88(-/-) mice showed levels of submucosal inflammation and edema similar to WT mice, they were impaired in the development of mucosal inflammation, along with infection-induced epithelial damage, proliferation, and goblet cell depletion. MyD88(-/-) mouse tissues also had fewer submucosal fibroblasts and 60% less collagen. We noted that cyclooxygenase (Cox)-2 expression was MyD88-dependent, with numerous Cox-2-positive cells identified in fibrotic regions of WT mice at postinfection day 7, but not in MyD88(-/-) mice. Treatment of WT mice with the Cox-2 inhibitor rofecoxib (20 mg/kg) significantly reduced fibroblast numbers and collagen levels without altering colitis severity. In conclusion, MyD88 and Cox-2 signaling play roles in intestinal fibrosis during Salmonella-induced enterocolitis.