In this study, a colitis mouse model induced by dextran sulfate sodium (DSS) was used to investigate the mechanisms of action of an extract of crude polysaccharides (POL) from Physalis pubescens L. as a dietary intervention for colitis. Our results showed that the administration of POL prior to DSS-induced colitis protected the colon mucosal layer; maintained intestinal barrier integrity; alleviated oxidative damage; and lowered neutrophil infiltration by downregulating intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression. More importantly, POL pretreatment reduced the expression of the proinflammatory factors tumor necrosis factor-α, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), thereby modulating the nuclear factor-κB/iNOS-COX-2 signal transduction pathway. In addition, POL reversed DSS-induced gut dysbiosis, accompanied by reducing the relative abundance of Helicobacter, Mucispirillum, and Erysipelatoclostridium. In conclusion, POL ameliorated DSS-induced intestinal injury in mice, indicating that POL could be a useful dietary nutrient to protect against colitis. PRACTICAL APPLICATION: Physalis pubescens L. is an edible fruit. The results of this study show that the intervention with Physalis pubescens L. crude polysaccharides may help prevent ulcerative colitis.