Interleukin‐1beta (IL‐1β) and interleukin‐17A (IL‐17A) have strong pro‐inflammatory activities that are involved in inflammatory bowel diseases (IBDs). Mesenchymal stem cell (MSC) therapy is considered a promising treatment for IBD. This study was performed to understand the role of rat Nlrp3 inflammasome, Hmgb1, and pro‐ inflammatory cytokines (IL‐1β and IL‐17a) in the pathogenesis of IBD. Also, to evaluate the role of human umbilical cord blood‐MSCs (hUCB‐MSCs) in the management of IBD. The rats were in four groups: normal controls, indomethacin‐ induced IBD group, indomethacin‐induced IBD rats that received phosphate‐ buffered saline (PBS), and the IBD group that received hUCB‐MSCs as a treatment. The messenger RNA (mRNA) expression levels of rat Nlrp3, Hmgb1, IL‐1β, and IL‐17a were evaluated by quantitative real‐time polymerase chain reaction. Histopathological examination of the small intestinal tissues of the studied rats was performed. There was a significant upregulation of the rat Nlrp3, IL‐1β, IL‐17a mRNA expression (p < 0.001 for the three parameters), and Hmgb1 (p < 0.05) in the untreated IBD group compared to the normal control group. In the MSC‐treated group, IL‐1β, IL‐ 17a, and rat Nlrp3 mRNA expression significantly decreased compared to both the untreated IBD group and PBS group (p < 0.05 for all). hUCB‐MSCs ameliorated IBD in rats by downregulating the pro‐inflammatory cytokines (IL‐1β and IL‐17a) and other inflammatory mediators such as Hmgb1 and rat Nlrp3.