Acute severe ulcerative colitis (ASUC) remains a clinical challenge associated with considerable morbidity, including colectomy. Upadacitinib (UPA), a selective Janus kinase (JAK)-1 inhibitor, is approved for moderate-to-severe ulcerative colitis in patients intolerant or not responding to tumor necrosis factor-alpha inhibitors. It has also increasingly been used off-label for ASUC. We performed a systematic review of all available literature on UPA in ASUC. We identified 11 studies, with a pooled total of 55 patients. Most patients experienced rapid and sustained improvement. Colectomy rate at 90 days was 16.3%. Among those who did not get colectomy, 80% were in steroid-free remission at follow-up. The reported adverse events were low, including 2 venous thromboembolic events. Overall, UPA appears to represent a safe and effective therapy for ASUC.