PURPOSE: Acute severe ulcerative colitis (ASUC) is a medical emergent condition, and approximately one-third of patients with ASUC do not respond to corticosteroid. Whether small molecule drugs are efficient and safe for salvage therapy of ASUC is not well-understood. METHODS: Consecutive patients with ASUC who failed responding to first-line corticosteroid were retrospectively enrolled. Clinical, laboratory, endoscopic, and pathological data were analyzed. RESULTS: Five Asian male patients (median age of 38.9 years old) with ASUC who received salvage therapy with upadacitinib were enrolled. The mean (+/- standard deviation) disease duration was 3.44 (+/- 3.30, 0.53 ~ 7.88) years. Baseline Montreal disease extent, C-reactive protein, and erythrocyte sedimentation rate were four (80%) E3 and one (20%) E2 disease, 40.54 (+/- 74.26) mg/dl, and 24.50 (+/- 19.09) mm/h, respectively. Daily upadacitinib 45 mg was prescribed for 56 days in all patients. Clinical response, clinical remission, corticosteroid-free remission, and endoscopic improvement at weeks 8 and 12 were achieved in five (100%) and five (100%), four (80%) and five (100%), four (80%) and five (100%), and four (80%) and five (100%) patients, respectively. One (20%) patient achieved histo-endoscopic remission at week 24. None of them had re-hospitalization or colectomy during the follow-up period but one patient developed penile simplex-1 infection which resolved after topical antiviral ointment without upadacitinib discontinuation. CONCLUSIONS: Upadacitinib is an efficient salvage therapy for patients with ASUC. Further investigations are essential to assess long-term durability, safety profile, and viability as a bridging regimen in the treatment of ASUC.