Objective β-arrestins are intracellular scaffolding proteins that modulate a variety of cell biological processes. Two types of β-arrestins have been identified: β-arrestin1 and β-arrestin2. A recent study has showed that deficiency of β-arrestin1 protect mice from colitis. The aim of the study was to investigate the role of β-arrestin2 in experimental colitis. Methods Wild-type (WT) and β-arrestin-2 knockout (KO) mice (8 to 10 weeks) we subjected to colitis induced by dextran sulfate sodium (DSS). The clinical signs (based on body weight, stool consistency, the presence of occult blood,) were observed, and gross pathology and histopathology of the colon and gastrointestinal motility were performed for the evaluation. Results DSS treatment induced a dramatic body weight loss, diarrhea and hemafecia in both WT and KO mice. However, the KO mice present with higher clinic score and exhibited more pronounced colonic shortening, crypts damage, goblet cell loss, inflammatory cell infiltration and gastrointestinal motility disability than WT mice. Conclusion Contrary to β-arrestin-1, β-arrestin-2 protected mice from experimental colitis.