Background: Inflammatory Bowel Disease (IBD), which includes Crohn's Disease (CD) and Ulcerative Colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract and a relapsing-remitting disease course. Understanding the risk factors for relapse can help in tailoring management strategies for patients. Methods: This prospective longitudinal study involved 500 patients with IBD, split equally between CD and UC, who were in remission at study onset. Over two years, data on genetic markers, environmental and lifestyle factors, microbiome composition, medication adherence, and psychological stress were collected and analyzed to identify their association with disease relapse. Results: Significant predictors of relapse included the presence of the NOD2/CARD15 genetic marker in CD (28% presence, p < 0.001), smoking (OR 2.9, p < 0.001), highfat diet (OR 2.3, p < 0.001), alterations in microbiome composition (p < 0.001), low medication adherence (HR 3.1, p < 0.001), and high psychological stress (HR 2.7, p < 0.001). These factors were independently and cumulatively significant in multivariable analyses. Conclusion: The study highlights the complex interplay of genetic, environmental, microbial, and psychosocial factors in the relapse of IBD. Addressing these factors through targeted interventions could substantially reduce the burden of disease relapses.