Abstract Background Acute severe ulcerative colitis (ASUC) often requires rescue therapy to prevent colectomy. Despite novel therapies, optimal strategies and long-term outcomes are uncertain. This systematic review with meta-analysis aimed to determine pooled colectomy rates after medical treatments for ASUC and identify factors associated with colectomy risk. Methods A meta-analysis was performed according to PRISMA guidelines. MEDLINE, EMBASE, and Cochrane databases were searched to March 2025 for randomized and non-randomized controlled trials, comparative and single-arm cohort studies in adults with ASUC treated with corticosteroids, rescue therapies (infliximab, cyclosporine, JAK inhibitors), or sequential approaches. Colectomy rates were analysed at multiple time-points: in hospital, 3, 6, and 12 months, and last follow-up. The primary outcome was 12-month colectomy. Pooled proportion meta-analyses and meta-regression analyses examining associations between treatment type, publication year, study design, patient characteristics [age, disease duration, baseline medications, C-Reactive Protein (CRP), albumin, extent of colitis] and 12-month colectomy rates were performed. Results A total of 124 arms from 75 studies were included. The pooled 12-month colectomy rate was 30.5% (95% CI 26.3–34.9; 3,114 patients), varying by therapy: sequential rescue 56.8%, cyclosporine 40.9%, high-dose infliximab 27.3%, standard-dose infliximab 24.0%, and JAK inhibitors 17.9%. The in-hospital colectomy rate was 16.5% (95% CI 13.8–19.5), highest with cyclosporine (21.7%) and lowest with JAK inhibitors (1.9%). At 3 months, the pooled colectomy rate was 20.2% (16.8–23.8), higher for sequential rescue (38.6%) and cyclosporine (27.8%). At 6 months, the pooled rate was 27.3% (21.4–33.6), highest with sequential rescue (43.2%). Meta-regression showed publication year was inversely associated with 12-month colectomy (coefficient –0.013, 95% CI –0.020 to –0.007, p < 0.001). All other interventions had significantly lower rates than sequential rescue (–0.280, p = 0.029). Higher baseline steroid use increased colectomy risk (coefficient 0.001, p = 0.020). Study design, steroid-refractory status, prior biologic use, age, disease duration, inflammatory markers, and disease extent were not significant. Conclusion Colectomy rates in ASUC remain considerable and are highest with sequential rescue. These findings suggest that novel therapies and strategies are needed to improve patient outcomes. Conflict of interest: Barberio, Brigida: Brigida Barberio: has served as speaker for Abbvie, Agave, Alfasigma, AGpharma, Johnson & Johnson, Eli Lilly, MSD, Pfizer, Procise, Sofar, Takeda, Unifarco. BB has served as consultant for Abbvie, Eli Lilly, Johnson & Johnson. Yuan, Yuhong: No conflict of interest Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Vuyyuru, Sudheer: No conflict of interest