Ulcerative colitis, a chronic inflammatory bowel disease, is often associated with mental health disorders exacerbated by chronic stress. Environmental enrichment has been shown to alleviate stress and inflammation in mice, therefore we hypothesized that it may mitigate the adverse behavioral and neurobiological outcomes associated with experimental colitis. To study this, male and female mice were kept in 2 different housing conditions, conventional small cages (SE) or an enriched environment (EE), for 8 weeks. Subgroups were treated with dextran sulphate sodium (DSS) to induce experimental colitis and readouts comprised a battery of behavioral tests and inflammation assessments. Analysis revealed that male DSS-treated EE-housed mice experienced less weight loss, had less colonic inflammation and had a lower disease activity index than SE-housed animals. In contrast, DSS-treated females in EE exhibited more severe symptoms than those in SE, suggesting sex-dependent differences. Both male and female DSS-treated mice, irrespective of housing, displayed reduced locomotion in the open field test. DSS-treated males in SE showed less anxiety-like behavior in the elevated plus maze compared to controls, an effect not observed in EE. DSS-treated females displayed increased anxiety-like behavior regardless of housing, and a decrease in social behavior. DSS-treated animals also showed increased numbers of innate immune cells in colon, brain and blood, indicating inflammation all along the gut-brain axis. In conclusion, EE appears to provide partial protection against experimental colitis in males but exacerbates inflammation in females. Further experiments will clarify which biological pathways contribute to the observed sex-dependent effects.