Ulcerative colitis, a chronic inflammatory condition that affects the colon from rectum to caecum, is characterized by periods of increased bowel movements, blood in feces, rectal urgency, tenesmus, and abdominal pain, with periods of remission and flares of disease, which negatively impact quality of life. A number of therapeutic options are available for patients with moderate-to-severe ulcerative colitis, however, no clear treatment algorithm exists. Therapeutic goals include short-term benefits for patients (i.e., the reduction/absence of symptoms, essentially stool frequency and rectal bleeding) and long-term benefits (i.e., sustained clinical remission, steroid-free remission, and mucosal healing). Therapies currently approved and available for the treatment of moderate-to-severe ulcerative colitis include monoclonal antibodies such as those targeting anti-tumor necrosis factor α (i.e., infliximab, adalimumab, golimumab), anti-adhesion molecules (i.e., vedolizumab), anti-interleukin 12/23 agents (i.e., ustekinumab), and Janus Kinase inhibitors (i.e., tofacitinib). Surgical approaches should also be considered in patients refractory to medical therapy or with complications (including toxic megacolon or colonic dysplasia/cancer). This review provides an overview of currently available treatment options for patients with moderate-to-severe ulcerative colitis and summarizes factors that should be considered during the therapeutic decision.