Background and Aims <p>Histological differences are among the characteristics that divide Crohn’s disease (CD) from ulcerative colitis. Granulomas are one feature known to develop in a subset of patients with CD, though their exact role in prognosis is relatively limited. Therefore, there is an unmet need to further understand the features that predict patterns in disease courses for people with CD.</p> Methods <p>A comprehensive literature search was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Databases used for the search were EMBASE, PubMed, CINAHL, Scopus, and Web of Science. Two reviewers independently reviewed abstracts and full text for inclusion. Overall, 46 studies were included for data collection and quality assessment.</p> Results <p>The 46 studies included 37 cohort analyses, four systematic reviews (three with meta-analysis), four cross-sectional studies, and one case–control report. Common exposure and outcome variables included age, disease location and behavior, clinical severity, medication utilization, and surgical requirement. There was considerable risk for bias in accordance with the Critical Appraisal Skills Programme tool, with only 26 studies having met ≥ 80% of high-quality assessment criteria. Varying relationships were observed between granulomas and clinical aspects of disease such as phenotype, severity, and medication utilization.</p> Conclusion <p>This systematic review aimed to centralize the current literature and provide insight into the possible prognostic value of granulomas in CD. Several studies suggested clinical relevance; however, larger studies that adjust for confounders are needed to truly elucidate the underlying pathophysiology and significance of granulomatous CD.</p>