Inclusion Criteria:
* Patient ≥ 18 to 75 years of age at the time of consent
* Diagnosis of ulcerative colitis (verified by a typical clinical history as well as characteristic appearance on endoscopy and histology)
* Meeting the following definition of acute severe ulcerative colitis as defined as having ≥ 6 bowel movements per day with visible blood in the 7 days prior to Day 0 plus at least one of the following:
i. Temperature \> 37.8 Celsius(C) per patient report or documented in Electronic Health Record (EHR) in the 7 days prior to Day 0.
ii. Pulse ≥ 90 beats per minute (BPM) per patient report or documented in EHR iin the 7 days prior to Day 0 iii. Hemoglobin ≤ 10.5 grams per deciliter (g/dL) in the 7 days prior to Day 0 iv. Erythrocyte sedimentation rate ≥ 30 millimeters per hour (mm/h) in the 7 days prior to Day 0 v. C-reactive protein ≥ 3.0mg/dL in the 7 days prior to Day 0 vi. Fecal calprotectin \>782 Milligrams per kilogram (mg/kg) in the 7 days prior to consent.
vii. Oral corticosteroid use for ≥ 7 days in the month prior to consent at a dose equivalent to ≥ 20 milligrams per day (mg/day)
* For a person of reproductive/childbearing potential (i.e., presence of intact ovaries and fallopian tubes and are considered premenopausal by standard assessment), a negative lab-based (serum/urine) pregnancy test is required.
* For a person of reproductive potential (i.e., presence of intact ovaries and fallopian tubes) and has childbearing potential, intent to use at least one effective method of birth control from study Day 0 through the end of blinding or at least 30 days after the last dose of upadacitinib or week 48, whichever occurs most recently. A person without reproductive or childbearing potential does not require an intent to use effective birth control.
* Participants enrolled in the outpatient cohort must be under the care of an outpatient gastroenterologist affiliated with the University of Michigan.
* Ability to take oral medication and be willing to adhere to the study intervention regimen.
* Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily bowel movement symptoms surveys, and other study procedures.
* Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study.
Exclusion Criteria:
* On IV corticosteroids for \> 72 hours immediately prior to enrollment continuously (at any institution) which is equivalent to a cumulative dose of 180mg of IV Methylprednisolone in the 3 days prior to enrollment.
* Patients with a prior exposure upadacitinib. Previous exposure to other Janus kinase (JAK) inhibitors (e.g., tofacitinib, baricitinib, or filgotinib) are permissible.
* History of clinically significant (per investigator's judgment) drug or alcohol abuse within the last 6 months prior to Baseline. (Note: A Urine Drug Screen does not need to be performed).
* A history of two or more prior episodes of herpes zoster, or one or more episodes of disseminated herpes zoster.
* Patients with ongoing severe active infection (as determined by the study team) per investigator. Patients with active serious infection(s) requiring treatment with intravenous anti-infectives or oral/intramuscular anti-infectives may consider infectious disease clearance.
* Active tuberculosis (TB) or untreated latent TB as described in the protocol.
* In participants that tested positive for Coronavirus disease 2019 (COVID-19), at least 5 days must have passed between a COVID-19 positive test result and the baseline visit of asymptomatic participants. Participants with mild/moderate COVID-19 infection can be enrolled if fever is resolved without use of antipyretics for 24 hours and other symptoms improved, or if 5 days have passed since the COVID-19 positive test result (whichever comes last). Participants may be rescreened if deemed appropriate by the investigator based upon the participant's health status.
* Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting, or aorto-coronary bypass surgery.
* Known hypersensitivity to the following drugs or constituents (and its excipients): methylprednisolone, prednisone, upadacitinib, or upadacitinib placebo. The following ingredients can be found in upadacitinib and upadacitinib placebo: colloidal silicon dioxide, hypromellose, iron oxide yellow and iron oxide red, magnesium stearate, mannitol, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, talc, tartaric acid and titanium dioxide. This includes a known or suspected hypersensitivity to cow's milk for patients expected to be in the inpatient cohort (component of methylprednisolone).
* Participants that are currently pregnant or breastfeeding. Participants with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of pregnancy or other pathological causes of borderline results and a serum pregnancy test ≥ 3 days later to document continued lack of a positive result. Participants with a urine pregnancy test at Baseline that is borderline or ambiguous must have a serum pregnancy test performed. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
* Participants that have received any live vaccine with replicating potential within 30 days prior to the first dose of study drug or are expected to need a live vaccination with any replicating potential during study participation or within 30 days of study completion.
* Patients that meet diagnostic criteria for toxic megacolon as determined by the study and treatment team. Patients are expected to have dilation of the transverse colon \> 6 centimeters (cm) or cecum/right colon \> 9cm and three of the following signs of systemic toxicity (Temperature \> 38◦C, Heart rate (HR) \> 120 beats per minute (BPM), white blood cells (WBC) \> 10500/microliter (µL), Hemoglobin \< 10.5mg/dL) and one of the following (dehydration, altered mental status, severe electrolyte disturbances, or hypotension)
* Patients with active Cytomegalovirus (CMV) colitis as defined as having \> 5 CMV inclusion bodies per high powered field in any one ulcer at baseline. If CMV colitis is confirmed, the patient can remain in the trial if permissible by the infectious disease and primary treatment team and if concomitant anti-viral therapy is initiated.
* Patients that had received any investigational agent or procedure within 30 days or five half-lives prior to baseline, whichever is longer, or were enrolled in an interventional study.
* Patients with an active malignancy with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
* Patients that had a history of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy or were planning bowel surgery (partial colectomy is permissible)
* Patients with certain laboratory abnormalities suggestive of moderate or severe renal, hematological, or gastrointestinal/liver impairment (per protocol).
* History of or clinical evidence of liver cirrhosis
* History of inherited or acquired conditions that predispose to hypercoagulability (per protocol). Please note, that patients with a remote history of provoked thromboembolic event or recent thromboembolic event on systemic anticoagulation are NOT exclusionary.
* Active Hepatitis B Infection: Hepatitis B surface antigen (HBsAg) positive with detectable deoxyribonucleic acid (DNA) not on therapy. Patients with serologic evidence of a resolved prior hepatitis B virus (HBV) infection (i.e., HBsAg-negative and anti-HB Core-positive) or patients with HBsAg positive on suppressive HBV therapy with low DNA (\<105 copies/milliliter (mL) or \<104 IU/mL negative) are not exclusionary.
* Active Hepatitis C Infection: Hepatitis C Virus (HCV) ribonucleic acid detectable in any patient with anti-HCV antibody.
* Acquired Immunodeficiency Syndrome: Confirmed positive anti-human immunodeficiency virus (HIV) antibody with cluster of differentiation 4 (CD4) counts \<350 cells/microliter (uL) or Acquired Immune Deficiency Syndrome (AIDS)- defining opportunist infection.
* Solid organ or bone marrow transplant within 1 year or expected transplant within 6 months of randomization.
* Patients that had a history of spontaneous GI perforation (other than appendicitis or mechanical injury) or are at significantly increased risk of GI perforation per investigator's judgment.
* Actively receiving strong CYP3A4 inducers or inhibitors prior to the first dose of study drug or are expected to receive any of these medications during the study period. This includes grapefruit and grapefruit juice.
* The presence of any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery) as determined by the investigator. Procedures such as gastric banding that simply divide the stomach into separate chambers are not exclusionary.
* Patients that had a history of a clinically significant medical condition per protocol.
