Upadacitinib is a selective small molecule that inhibits Janus kinase (JAK) type 1. This molecule is administrated orally and is currently approved for the treatment of rheumatoid arthritis, atopic dermatitis, and psoriatic arthritis. Upadacitinib has been approved by the United States Food and Drug Administration for the induction and maintenance therapy of moderate-to-severe ulcerative colitis (UC) and is under investigation by the European Medicines Agency. Data from two induction and two maintenance Phase III randomized controlled trials (RCTs) proved the efficacy of upadacitinib in achieving clinical and endoscopic remission in patients with moderate-to-severe UC, regardless of previous inadequate response to other biologic therapies. The most frequently reported adverse events in the induction trials were acne, creatine phosphokinase increase, nasopharyngitis, headache, and anemia, while in the maintenance studies nasopharyngitis, elevation of creatine phosphokinase, UC exacerbation, upper respiratory tract infection, arthralgia, and anemia were reported. A limited proportion of upadacitinib-treated patients experienced adverse events of special interest, like herpes zoster infections or thromboembolic events, indicating a reliable safety profile. The aim of this review is to summarize the available evidence on upadacitinib in UC providing useful insights about the positioning of this drug in the therapeutic algorithm.