Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex pathogenesis and limited treatment options. Recently, necroptosis has been found to play a significant role in UC. This study aimed to investigate necroptosis-related mechanisms and hub targets in UC, and to screen natural potential inhibitors. Firstly, transcriptomic and single-cell analyses were used to explore the molecular and cellular mechanisms of necroptosis in UC and identify hub targets. Subsequently, virtual screening and molecular dynamics were performed. The results indicated that twenty-three necroptosis-related differentially expressed genes (DEGs) were predicted as diagnostic biomarkers in the best machine-learning model (GBM). Furthermore, four hub targets (IL1B, MLKL, STAT1, and BIRC3) were computationally prioritized and their overexpression might promote pro-inflammatory activity (neutrophils/M1 macrophages) while suppressing anti-inflammatory responses (Tregs/M2 macrophages), aggravating UC progression. Single-cell analysis revealed reduced epithelial cells and increased fibroblasts, endothelial cells, and immune cells in UC tissues, suggesting disruption of the intestinal epithelial barrier, exacerbation of fibrosis, and activation of the immune system. The high abundance of endothelial cells and monocytes expressing necroptosis-related DEGs suggested the important role of necroptosis in UC. Moreover, eight natural products were screened with strong binding affinity to MLKL, whose motion trajectories and energy trajectories reached equilibrium within 10 ns. Among them, the potential of trifolirhizin and curcumin as natural inhibitors was particularly prominent. Conclusively, this study computationally predicts four hub DEGs and eight potential natural necroptosis inhibitors, may provide a basis for future therapeutic exploration.