Background/Objectives: Evidence is needed on the real-world outcomes of upadacitinib in patients with ulcerative colitis. This systematic review and meta-analysis evaluated the real-world effectiveness of upadacitinib for active UC. Methods: The primary outcome was clinical remission evaluated at week 8. Secondary outcomes included response, steroid-free remission, biochemical remission, colectomy, and safety. A random-effects meta-analysis model was used to calculate the pooled effect sizes (percentages or incidence rates) of effectiveness and safety outcomes. Results: Twenty-four studies with 1388 patients were included. Ninety-four percent of patients had previously failed biologics or Janus kinase inhibitors (JAKi), including 53.2% with tofacitinib. Clinical remission at week 8 was achieved in 68.4% of patients (95% confidence interval 55.5-80.2). Clinical remission was achieved in 48.3%, 71.1%, and 64.6% of patients at weeks 2 to 6, 12 to 16, and 24 to 36, respectively. Response was achieved in 72.6%, 82.1%, and 78.7% of patients at weeks 2 to 6, week 8, and weeks 12 to 16, respectively. Steroid-free remission was achieved in 39% of patients at week 8. Upadacitinib results were unaffected by prior biologic or JAKi failure. Mean fecal calprotectin level decreased from 1485.0 micro/g at baseline to 454.8 micro/g post-treatment (p < 0.01). The mean CRP level decreased from 12.3 mg/L at baseline to 4.4 mg/L post-treatment (p = 0.02). The incidence rates of colectomy, serious adverse events, and herpes zoster were 13.3, 2.3, and 1.7 per 100 patient-years, respectively. Conclusions: This meta-analysis confirms the effectiveness and safety of upadacitinib in a highly treatment-refractory population of UC patients.