Background and Aim: The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available. This systematic review and meta-analysis synthesized randomized controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. Methods: A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI), and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation). Results: We included 40 RCTs (13 therapies, 14,369 patients). Thirty-two trials provided data in induction and twenty-eight in maintenance. During induction, all biologic therapies, except mirikizumab and filgotinib 100 mg, demonstrated superiority over placebo (RR 2.02, 95% CI: 1.76–2.31, I² = 72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78–8.09). For mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI: 2.11–4.13, I² = 61%), except filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI: 2.49–42.11). In maintenance, all therapies showed superiority over placebo for endoscopic improvement. For mucosal healing all therapies were superior to placebo, except risankizumab. Upadacitinib 30 mg showed the highest efficacy (RR 4.01, 95% CI: 1.81–8.87). Conclusions: Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endpoints. Standardized outcome definitions and further head-to-head RCTs are essential to strengthen confidence in our findings.