Inclusion Criteria:
* Age 18 to 80 years old (inclusive) at time of consent
* Understand and sign the written voluntary informed consent form prior to any protocol specific procedures
* History of established UC for \>3 months as determined by standard clinical criteria
* Active UC defined as a modified Mayo score of 5-9 with a rectal bleeding sub score \[RBS\] ≥1 and Mayo endoscopic score \[MES\] ≥2
* Participant will have a minimum disease extent of at least 5 cm proximal from the anal verge
* Subjects must be on stable doses of concomitant medications, defined as:
* Participants on oral corticosteroids must be on a stable dose \>2 weeks (dose not exceeding 20 mg/day prednisone, 9mg/day of budesonide, or equivalent) prior to screening
* Participants on methotrexate (MTX), azathioprine (AZA), or 6-mercaptopurine (6-MP) must be on treatment at a stable dose \>4 weeks prior to screening and until end of study
* Participants on oral 5-aminosalicylates, mesalamine, or sulfasalazine must be on a stable dose for \>4 weeks prior to screening and until end of study
* Probiotics or anti-diarrheal at a stable dose ≥ 2 weeks prior to Screening and until the end of study
* Participants who have been diagnosed with UC for ≥8 years must be up to date on their colorectal cancer screening per local guidelines by the time of randomization.
Exclusion Criteria:
* Diagnosis of inflammatory bowel disease unclassified (IBD-U) or Crohn's colitis
* Previously received VDZ or etrolizumab (another anti-integrin biologic therapy)
* Receiving corticosteroids at a dose \>20mg/day of prednisone within two weeks prior to enrollment
* Participants who have been exposed to more than one advanced therapy medication (biologic or small molecule drug) before enrollment will be excluded
* Receiving or planned concomitant biologic or small targeted small molecule advanced therapy (tumor necrosis factor antagonist, interleukin \[IL\]-12/23 antagonist, IL-23 antagonist, Janus kinase \[JAK\] inhibitor and/or sphingosine-1-phosphate \[S1P\] receptor modulator) with vedolizumab
* Any calcineurin inhibitor use within 4 weeks prior to screening (e.g., cyclosporine, tacrolimus)
* Participant with known hepatitis B or C infection
* Participant with active or latent tuberculosis (that has not been adequately treated)
* Participant has any active infection
* Participant has fecal sample positive for enteric infection at screening
* History of prior colectomy or ileal pouch anal anastomosis
* Participants with fulminant UC, toxic megacolon, or hospitalized for UC currently or within prior 2 weeks
* Severe lab abnormalities including hemoglobin \< 8.0 g/dl, albumin \< 3.0 g/dl, platelets \< 100/mcl, AST \> 2X upper limit of normal (ULN), ALT \>2X ULN, total bilirubin \>1.5X ULN
* Participant with history of colon cancer or colonic dysplasia not adequately treated (i.e. polyp removed)
* Any serious underlying disease other than UC that in the opinion of the investigator may interfere with the participant's ability to participate fully in the study or would compromise participant safety (such as any unstable or uncontrolled medical disorder, class III or IV congestive heart failure, demyelinating disease)
* History of primary sclerosing cholangitis
* Renal impairment and reduced creatinine clearance defined as estimated glomerular filtration rate GFR (eGFR)\<60mL/min
* History of chronic liver disease (autoimmune hepatitis, cirrhosis, etc.)
* Currently requiring total parental nutrition
* History of solid organ transplantation
* History of malignancy or lymphoproliferative disorder in the prior 5 years, other than
* adequately treated localized carcinoma in situ of the cervix or nonmetastatic squamous
* cell carcinoma, or nonmetastatic basal cell carcinoma of the skin.
* History of venothromboembolism (DVT or PE) or known inherited or acquired hyper coagulation disorder
* Currently taking anti-platelet agent (other than aspirin) or anti-coagulant (coumadin,
* rivaroxaban, etc.)
* History of human immunodeficiency virus (HIV) infection
* Participant is pregnant or lactating or actively trying to become pregnant