In the present study, we showed the protective effect of tiliroside on dextran sodium sulfate (DSS)- and 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and uncovered a novel mechanism of tiliroside-regulating macrophage polarization via HIF-1α-dependent reprogramming of the glucose metabolic pathway. This evidence concerns the gene HIF1A and colitis.