Objective To explore key genes and mechanisms of depression aggravating Crohn disease. Methods In March 2023, the Public Health Genomics and Precision Health Knowledge Base and Gene Expression Omnibus database were used to identify the overlapping differentially expressed genes between Crohn disease and depression and the key genes were screened by Metascape, STRING, Cytoscape, and protein interaction network analysis. The Gene Expression Omnibus database was used to analyze the correlations between key genes and clinical pathologies such as Crohn Disease Endoscopic Index of Severity and intestinal microvilli length. Results There were 137 overlapping differentially expressed genes between Crohn disease and depression, and 25 key genes were further screened out. Among them, CREB1, FKBP5, MAPT, NTSR1, OXTR, PROK2, POMC, HTR2B, and PPARGC1A genes were significantly correlated with multiple clinical parameters. The functions of PROK2 and PROK2-related genes were mainly enriched in neutrophil and granulocyte migration, neutrophil and granulocyte chemotaxis, etc. Conclusions There are 25 key genes, especially CREB1, FKBP5, MAPT, NTSR1, OXTR, PROK2, POMC, HTR2B, and PPARGC1A, that possibly contribute to the establishment and deterioration of Crohn disease caused by depressive disorder. Among these genes, PROK2 showes the possibility of regulating immune cell (neutrophils and CD8+ T cells) infiltration.