BACKGROUND: This systematic review and meta-analysis evaluated the incidence of serious adverse events (SAEs) in patients with Crohn's disease (CD) and ulcerative colitis (UC) treated with upadacitinib and examined secondary adverse events. METHODS: A comprehensive search of PubMed, Embase and Cochrane Library was conducted to identify randomized controlled trials (RCTs) comparing upadacitinib with placebo in adults with inflammatory bowel disease (IBD). The primary outcome was the incidence of SAEs, while secondary outcomes included specific adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. RESULTS: Six RCTs, including 2611 patients, were analyzed. The incidence of SAEs did not significantly differ between upadacitinib (6.1%) and placebo (7%) (RR = 0.77; 95% CI: 0.50-1.20; p = 0.25). Secondary outcomes showed no significant differences in serious infections, hepatic disorders, nasopharyngitis or herpes zoster. However, neutropenia (RR = 5.63; 95% CI: 1.90-16.65; p = 0.0002) and creatine kinase elevation (RR = 2.34; 95% CI: 1.22-4.47; p = 0.01) were higher with upadacitinib, while anemia (RR = 0.36; 95% CI: 0.27-0.48; p < 0.00001) and arthralgia (RR = 0.47; 95% CI: 0.30-0.75; p = 0.001) were reduced. CONCLUSION: Upadacitinib did not increase the overall risk of SAEs in IBD patients, with a notable reduction in anemia and arthralgia. However, the higher risks of neutropenia and CK elevation underscore the importance of monitoring. Further research is necessary to assess long-term safety, particularly regarding rare but serious events such as thromboembolism.