Ginsenoside Rg1 is a major active constituent of Panax ginseng and possesses anti-inflammatory effects. It has been reported to have therapeutic effects on various diseases. In the present study, we investigated the role of ginsenoside Rg1 in dextran sodium sulfate (DSS)-induced mouse colitis. Our results showed that ginsenoside Rg1 markedly reduces proinflammatory cytokines release upon DSS stimulation of mouse dendritic cells, that ginsenoside Rg1 suppresses IL-1β (Interleukin 1 beta) and TNF-α (Tumor necrosis factor alpha) release via up-regulation of NLRP12 (NACHT, LRR and PYD domains-containing protein 12) expression, and that ginsenoside Rg1 significantly decreases the inflammatory response to DSS-induced mouse colitis, as evidenced by increased body weight, reduced colonic damage scores and disease activity index (DAI), and lowered proinflammatory cytokines levels. These results highlight the potential therapeutic use of ginsenoside Rg1 as an anti-inflammatory agent in the treatment of colitis.