Crohn's disease (CD) is a chronic systemic inflammatory disease that mainly affects the intestine, accompanied by extraintestinal symptoms and immune problems. The progression of the disease may cause permanent damage to the structure and function of the intestine. Due to unclear early symptoms and lack of precise detection methods, early diagnosis of CD is difficult. Many patients were diagnosis at late stage, which may lead to delayed treatment and increased risk of complications. Identifying hub genes related to CD and using them to predict CD is of great significance. DEG and WGCNA were employed to identify key genes associated with CD and to detect modules significantly linked to the disease. GO and KEGG analyses were conducted to explore the functions of these identified genes. Additionally, MR method was utilized to assess the causal relationships between the most significant gene and CD. WCGNA identified 3240 differentially expressed genes, with the magenta module being the most significant among the nine clustered modules. The enrichment of GO and KEGG pathways indicates that the hub genes in the magenta module are related to the positive regulation of heme binding, tetrapyrrole binding, carboxylic acid binding, organic acid binding, IL-17 signaling pathway, and amoebiasis pathway. The Top 5 hub genes are CXCL1, LCN2, NOS2, S100A8, and DUOX2. Mendelian randomization analysis found a significant correlation between CXCL1 and CD. The study screened five potential biomarker genes in CD patients using a bioinformatics approach and Mendelian randomization study. Our results provided insights into CXCL1, LCN2, NOS2, S100A8, and DUOX2 in CD and suggested that CXCL1 may potentially be the optimal biomarker that could be a relatively easy path to clinical translation.