Metabolic reprogramming has recently been recognized as related to immune disorders in ulcerative colitis (UC), but the specific metabolic pathways and genes involved remain unclear. Here, Mendelian randomization confirmed that mannose and mannonate exhibited a negative causal relationship with UC, and that the immune cell phenotype HLA DR on CD33dim HLA DR+ CD11b− mediated the effect of mannonate on UC. Bulk RNA sequencing data revealed that mannose metabolism abnormity is critical for driving the innate and acquired immune response. A well-performing diagnostic model related to mannose metabolism was constructed using SVM analysis, achieving an AUC-ROC value of 0.987 in the training set and an AUC-ROC value of 0.899 in the validation set. Single-cell analysis revealed that epithelial cells in which the mannose metabolism pathway was inactivated demonstrated increased intercell communication with myeloid cells, T cells, and B cells. In vitro experiments confirmed that KHK and AKR1B10 were suppressed under inflammatory stimulation, which may hinder mannose-related metabolism. This study elucidates the protective role of mannose metabolism in UC and provides a novel gene signature for diagnosis and treatment.