BACKGROUND: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by dysregulated mucosal immune responses. Although the precise cause of ulcerative colitis is yet unknown, immune system disruptions, environmental factors, and genetic predispositions all play a role in its pathogenesis. In an Egyptian patient population, this study is the first to examine a possible link between ulcerative colitis (UC) and the Interleukin-37 (IL-37) gene polymorphism (rs3811047). METHODS: This case-control study enrolled a total of 80 participants, comprising 40 patients with ulcerative colitis (UC) and 40 healthy controls. Serum levels of interleukin-37 (IL-37) were quantified using ELISA. Additionally, genotyping of the IL-37 single nucleotide polymorphism rs3811047 was performed using real-time PCR. RESULTS: Patients with ulcerative colitis (UC) had a significantly higher median serum IL-37 levels (90.25) compared to controls (70.00) (*p* = 0.004). Furthermore, IL-37 levels demonstrated a statistically significant positive correlation with the severity of the disease as assessed by the Partial MAYO score (*p* = 0.004), with the highest concentrations observed in severe cases relative to moderate, mild, or remission stages. Genetic analysis of the rs3811047 polymorphism revealed a higher prevalence of the GG genotype in UC patients compared to controls. A recessive genetic model showed a robust association with UC susceptibility (*p* = 0.018), whereas neither the dominant model nor individual allele frequencies (A vs. G) reached statistical significance (*p* > 0.05).