The options for medical management of acute severe steroid-refractory ulcerative colitis (UC) are limited. Recent guidelines caution against use of sequential rescue therapy in the setting of failed medical management with an initial salvage therapy. A systematic review was conducted to assess the outcomes of sequential rescue therapy with infliximab (IFX) and calcineurin inhibitors like cyclosporine (CsA) or tacrolimus (Tac) in patients with steroid refractory UC. A literature search identified studies that investigated treatment with IFX and CsA or Tac in acute severe UC. The primary outcome was short term symptomatic response to treatment. Secondary outcomes included adverse drug reactions, serious infections, mortality, rates of remission, and colectomy at 3 months and 12 months. Response rates with 95% confidence intervals (CI) are reported. Overall, 10 studies with 314 participants were eligible for inclusion. After sequential treatment patients achieved short-term treatment response in 62.4% (95% CI, 57.0%–67.8%) of cases and remission in 38.9% (95% CI, 33.5%–44.3%). Colectomy was required in 28.3% (95% CI, 21.7%–34.5%) of patients at 3 months and 42.3% (95% CI 36.0–48.6) at 12 months. Adverse events were encountered by 23.0% (95% CI, 17.7%–28.3%) of patients, including serious infections in 6.7% (95% CI, 3.6%–9.8%) and mortality in 1% (95% CI, 0%–2.1%). Our data summarizing experience from observational studies suggest that the risk-benefit ratio of sequential rescue therapy in acute severe UC seems acceptable. In the setting of failure of corticosteroids and an initial rescue therapy for acute severe UC, consideration can be given to use of another salvage agent based on patient preferences and the safety of this experience from observational data. The sequence of IFX followed by calcineurin inhibitors, or vice versa, have similar treatment outcomes and adverse events. Precautions to minimize the risk of adverse events, including early assessment of treatment response, use of serum drug levels to guide initiation of therapy, and early weaning of concurrent corticosteroids is recommended.