BackgroundVedolizumab is approved for the treatment of moderately to severely active Crohn's disease (CD). Real‐world evidence is essential for understanding the effectiveness and benefit–risk profile of vedolizumab outside clinical trial settings.ObjectiveTo identify, systematically review and assess the real‐world effectiveness and treatment persistence of vedolizumab in patients with CD, particularly over long‐term follow‐up periods and among populations with differing treatment experience, and to compare with the treatment persistence of anti‐tumour necrosis factor (TNF)‐α treatment.MethodsLiterature searches were conducted to identify studies published from 2014 to 2022. Relevant congress searches were conducted (2015–2022) using Embase or by hand. Data on adults with CD treated with vedolizumab or anti‐TNFα treatment in a real‐world setting were extracted for meta‐analysis.ResultsData from 73 studies, including 29,894 patients with CD, reported ≥ 1 outcome of interest for this analysis. Vedolizumab treatment persistence rate was 65.3% (95% confidence interval [CI] 60.2–70.1) at 1 year and 54.8% (95% CI 43.9–65.3) at 2 years. The treatment persistence rate with vedolizumab versus anti‐TNFα treatment was 84.6% (95% CI 70.2–92.8) versus 75.3% (95% CI 69.7–80.2) at 1 year and 70.6% (95% CI 60.7–78.8) versus 64.6% (95% CI 56.7–71.8) at 2 years. The mucosal healing rate at 1 year was 40.6% (95% CI 34.2–47.3). Clinical remission rates were 39.4% (95% CI 33.9–45.1) at 1 year and 34.3% (95% CI 18.1–55.2) at 2 years. Corticosteroid‐free clinical remission rates were 33.2% (95% CI 28.5–38.3) at 1 year and 20.4% (95% CI 12.5–31.5) at 2 years. All clinical outcome rates were higher in biologic‐naive than in biologic‐experienced patients.ConclusionReal‐world use of vedolizumab was associated with favourable long‐term effectiveness and treatment persistence. Vedolizumab is a suitable first‐line biological option for biologic‐naive patients with CD.