Glycoprotein nonmetastatic melanoma protein B (Gpnmb) is a transmembrane glycoprotein, which negatively regulates the inflammatory responses of macrophages. However, the role of Gpnmb in intestinal macrophages remains to be fully elucidated. The present study aimed to investigate the expression of Gpnmb and its effects on colonic mucosal injuries associated with dextran sulfate sodium (DSS)‑induced colitis in BALB/c mice, DBA/2J (D2) mice lacking Gpnmb and Gpnmb‑transgenic DBA/2J mice (D2‑gpnmb+). The colonic expression of Gpnmb increased with the severity of DSS‑induced colitis in BALB/c mice, and macrophages infiltrating the inflamed mucosa were found to express Gpnmb. The D2 mice lacking Gpnmb exhibited more severe DSS‑induced colitis, which was accompanied by higher levels of pro‑inflammatory cytokines, including interleukin (IL)‑1β and IL‑6, compared with the D2‑gpnmb+ mice. Following lipopolysaccharide stimulation, macrophages from the D2 mice expressed higher levels of pro‑inflammatory cytokines and lower levels of IL‑10, compared with the D2‑gpnmb+mice. In addition, in the RAW264.7 murine macrophage cell line, knockdown of Gpnmb by small interfering RNA was associated with increased production of pro‑inflammatory cytokines, which were potentially mediated by the extracellular signal‑regulated kinase (ERK) and p38 signaling pathways. The results of the present study indicated that macrophages infiltrating injured mucosa express Gpnmb, and that Gpnmb‑positive macrophages may ameliorate inflammation in the intestinal mucosa by decreasing pro‑inflammatory cytokine production via the ERK and p38 signaling pathways.